FORMULATIONS and PHARMACOKINETICS OF DEUTERATED BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2

ABSTRACT

The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.

This application is a continuation of U.S. patent application Ser. No.14/245,024, filed Apr. 4, 2014, which is a continuation of U.S. patentapplication Ser. No. 14/030,322, filed Sep. 18, 2013, which claims thebenefit of priority of U.S. provisional application No. 61/702,586,filed Sep. 18, 2012, the disclosures of which are hereby incorporated byreference as if written herein in their entireties.

Disclosed herein are new pharmaceutical compositions comprisingbenzoquinoline compounds, methods to inhibit vesicular monoaminetransporter 2 (VMAT2) activity in a subject, and methods for thetreatment of chronic hyperkinetic movement disorders.

Tetrabenazine ((+/−)-cis-tetrabenazine, Nitoman®, Xenazine®, Ro 1-9569),is a racemic mixture of(3R,11bR)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,and(3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor.Tetrabenazine is commonly prescribed for the treatment of choreaassociated with Huntington's disease (Savani et al., Neurology 2007,68(10), 797; and Kenney et al., Expert Review of Neurotherapeutics 2006,6(1), 7-17).

d₆-Tetrabenazine ((+/−)-cis-d₆-tetrabenazine) is a racemic mixture of(3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-oneand(3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.d₆-Tetrabenazine is a selectively deuterium-substituted, stable,non-radioactive isotopic form of tetrabenazine in which the six hydrogenatoms on the two O-linked methyl groups have been replaced withdeuterium atoms (i.e. —OCD₃ rather than —OCH₃ moieties).

Tetrabenazine and its major metabolites alpha-dihydrotetrabenazine(α-HTBZ) and beta-dihydrotetrabenazine (β-HTBZ) are selective and potentinhibitors of the VMAT2. Scherman et al., Mol. Pharmacol. 1988,33(1):72-7. In humans, extensive hepatic metabolism of tetrabenazine toα-HTBZ and β-HTBZ by carbonyl reductase results in plasma concentrationsof tetrabenazine that are very low and are often below the limit ofdetection. Thus, α-HTBZ and β-HTBZ are thought to confer thepharmacological and therapeutic activity of orally administeredtetrabenazine in patients. In human plasma, α-HTBZ and β-HTBZ havehalf-lives of 7 hours and 5 hours, respectively (Xenazine® USPrescribing Information). Alpha(α)-HTBZ and β-HTBZ are each metabolizedinto pairs of mono-O-desmethyl metabolites (9-O-desmethyl-HTBZ and10-O-desmethyl-HTBZ) which are, in turn, conjugated by sulfonationand/or glucuronidation for excretion. The 9-O-desmethyl-β-HTBZmetabolite, which is derived from β-HTBZ, is also a major circulatingmetabolite. CYP2D6 is primarily responsible for O-demethylation ofα-HTBZ and β-HTBZ in humans.

d₆-Tetrabenazine has been designed with the intent to improve thepharmacokinetic profile of active metabolites α-HTBZ and β-HTBZ. The CYPmediated cleavage of the carbon-deuterium bonds within the trideuteratedmethyl groups (CD₃) of d₆-tetrabenazine is slower than the cleavage ofthe carbon-hydrogen bonds in the methyl groups (CH₃) of tetrabenazine,an effect that selectively attenuated O-demethylation of deuteratedα-HTBZ and β-HTBZ (d₆-α-HTBZ and d₆-β-HTBZ) in in vitro studies. Anincrease in the stability of deuterated α-HTBZ and β-HTBZ and acorresponding reduction of O-desmethyl metabolites have beendemonstrated in in vitro metabolism assays. In contrast, the conversionof tetrabenazine to its HTBZ metabolites does not involvecarbon-hydrogen bond cleavage and, as such, is not altered by thepresence of deuterium in the molecule.

The spectrum of metabolites produced by d₆-tetrabenazine is expected tobe similar to that in patients with reduced CYP2D6 metabolism whoreceive tetrabenazine. This is based on in vitro metabolism studies anda drug interaction study of tetrabenazine and paroxetine. In the druginteraction study, co-administration of tetrabenazine and paroxetineincreased systemic exposure to the α-HTBZ and β-HTBZ metabolites by 3-to 9-fold, respectively, compared to tetrabenazine alone (Xenazine® U.S.prescribing information). In vitro studies have demonstrated thatdigestion of deuterated α-HTBZ and β-HTBZ produced 69-87% less of theO-desmethyl metabolites compared to non-deuterated α-HTBZ and β-HTBZ.Administration of d₆-tetrabenazine to healthy volunteers led to anapproximate 2-fold increase in systemic exposure to α-HTBZ and β-HTBZand proportional reductions in O-desmethyl metabolites compared totetrabenazine. The increased exposure to α-HTBZ and β-HTBZ resultingfrom deuteration was not as pronounced as when tetrabenazine wasadministered with a strong CYP2D6 inhibitor such as paroxetine.Therefore, the metabolite profile associated with d₆-tetrabenazineshould be qualitatively similar to that observed in subjects withreduced CYP2D6 metabolism who receive tetrabenazine (e.g. patients onparoxetine) and no new metabolites are anticipated.

d₆-Tetrabenazine has been formulated as an extended release (ER) tablet.d₆-tetrabenazine ER is expected to provide a benefit to patients,through a combination of extended release and attenuated metabolism, byreducing peak-to-trough ratios and improving tolerability compared withtetrabenazine. Since the effect of deuteration is expected to be reducedin subjects with no functional CYP2D6 metabolism, e.g., poormetabolizers, it is likely that the inter-subject variability in thepharmacokinetics of α- and β-HTBZ will be lower for d₆-tetrabenazinethan for tetrabenazine. Thus, deuteration has the potential reduce theimpact of drug interactions and further improve the safety profile ofd₆-tetrabenazine ER. Finally, the increased half-life resulting fromdeuteration in conjunction with the extended release provided by theformulation, also has the potential to reduce dose frequency and improveoverall patient compliance as compared to the TID dosing regimencommonly used with tetrabenazine.

Novel pharmaceutical compositions have been discovered, together withmethods of synthesizing and using the compositions, including methodsfor the treatment of VMAT2-mediated disorders in a patient byadministering the compositions as disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Method of preparation of d₆-tetrabenazine extended releaseformulations and tetrabenazine extended release formulations.

FIG. 2: Dimensions of Gastro-Retentive Extended Release Large Tablet.

FIG. 3: Results of pharmacokinetic study of immediate-released₆-tetrabenazine and its metabolites d₆-α-HTBZ and d₆-β-HTBZ compared tonon-deuterated equivalents (tetrabenazine, α-HTBZ and β-HBZ) as well asthe corresponding O-desmethyl metabolites.

FIG. 4: Mean plasma concentrations of total (α+β)-HTBZ in each of aTBZ-fasted group, a Formulation A fed group, a Formulation B fed group,a Formulation A fasted group, and a Formulation B fasted group.

FIG. 5: Single dose mean plasma concentrations of total (α+β)-HTBZ from3 dose levels of d₆-tetrabenazine ER and one dose level oftetrabenazine.

FIG. 6: Steady state plasma concentrations of total (α+β)-HTBZ from 3dose levels of d₆-tetrabenazine ER and one dose level of tetrabenazine.

FIG. 7: Thermogravimetric analysis (TGA) profile of d₆-tetrabenazine,Form I.

FIG. 8: Differential scanning calorimetry (DSC) profile ofd₆-tetrabenazine, Form I.

FIG. 9: Powder X-ray diffraction (pXRD) profile of d₆-tetrabenazine,Form I.

FIG. 10: Thermogravimetric analysis (TGA) profile of d₆-tetrabenazine,Form II.

FIG. 11: Differential scanning calorimetry (DSC) profile ofd₆-tetrabenazine, Form II.

FIG. 12: Powder X-ray diffraction (pXRD) profile of d₆-tetrabenazine,Form II.

In certain embodiments, disclosed herein is a pharmaceutical compositioncomprising a deuterated analogue of tetrabenazine which yields, whenorally administered to a subject, at least one of the following:

an increase of the AUC of the total combined amount of deuterateddihydrotetrabenazine of at least 50% as compared to a pharmaceuticalcomposition comprising an equivalent amount of non-deuteratedtetrabenazine; or

an increase in half-life of deuterated dihydrotetrabenazine of at least50%;

as compared to a pharmaceutical composition comprising an equivalentamount of non-deuterated tetrabenazine.

In certain embodiments, the dihydrotetrabenazine is deuteratedalpha-dihydrotetrabenazine, deuterated beta-dihydrotetrabenazine, or acombination of deuterated alpha-dihydrotetrabenazine and deuteratedbeta-dihydrotetrabenazine.

In certain embodiments, the deuterated analogue of tetrabenazine isselected from the group consisting of(3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,(3R,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,(3S,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,and(3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.

In certain embodiments, the deuterated analogue of tetrabenazine isd₆-tetrabenazine.

In certain embodiments, the deuterated analogue of tetrabenazine is(+/−)-trans-d₆-tetrabenazine.

In certain embodiments, the pharmaceutical composition yields anincrease of the AUC of the total combined amount of deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine ofat least 100%; or

an increase in half-life of the total combined amount of deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine ofat least 70%;

as compared to a pharmaceutical formulation comprising an equivalentamount of non-deuterated tetrabenazine.

In certain embodiments, the pharmaceutical composition yields anincrease in half-life of the total combined amount of deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine atleast 100% as compared to a pharmaceutical composition comprising anequivalent amount of non-deuterated tetrabenazine.

In certain embodiments, the pharmaceutical composition yields yields areduced AUC or C_(max) of O-desmethyl metabolites of deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine ascompared to a pharmaceutical composition comprising an equivalent amountof non-deuterated tetrabenazine.

In certain embodiments, the AUC of 9-O-desmethyl metabolites ofdeuterated alpha-dihydrotetrabenazine and 9- and 10-O-desmethylmetabolites of deuterated beta-dihydrotetrabenazine is reduced by atleast 25%.

In certain embodiments, the AUC of 9-O-desmethyl metabolites ofdeuterated alpha-dihydrotetrabenazine and 9- and 10-O-desmethylmetabolites of deuterated beta-dihydrotetrabenazine is reduced by atleast 50%.

In certain embodiments, the AUC of 9-O-desmethyl metabolites ofdeuterated alpha-dihydrotetrabenazine and 9- and 10-O-desmethylmetabolites of deuterated beta-dihydrotetrabenazine is reduced by atleast 70%.

In certain embodiments, the C_(max) of O-desmethyl metabolites ofdeuterated alpha-dihydrotetrabenazine and deuteratedbeta-dihydrotetrabenazine is reduced by at least 25%.

In certain embodiments, the C_(max) of O-desmethyl metabolites ofdeuterated alpha-dihydrotetrabenazine and deuteratedbeta-dihydrotetrabenazine is reduced by at least 40%.

In certain embodiments, the C_(max) of O-desmethyl metabolites ofdeuterated alpha-dihydrotetrabenazine and deuteratedbeta-dihydrotetrabenazine is reduced by at least 55%.

In certain embodiments, the pharmaceutical composition yields a reducedratio of C_(max) to AUC of the total combined amount of deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine ascompared to a pharmaceutical composition comprising non-deuteratedtetrabenazine.

In certain embodiments, the ratio of C_(max) to AUC of the totalcombined amount of deuterated alpha-dihydrotetrabenazine and deuteratedbeta-dihydrotetrabenazine is reduced by at least 20% as compared to apharmaceutical composition comprising non-deuterated tetrabenazine.

In certain embodiments, the ratio of C_(max) to AUC of the totalcombined amount of deuterated alpha-dihydrotetrabenazine and deuteratedbeta-dihydrotetrabenazine is reduced by at least 40% as compared to apharmaceutical composition comprising non-deuterated tetrabenazine.

In certain embodiments, the C_(max) of the total combined amount ofdeuterated alpha-dihydrotetrabenazine and deuteratedbeta-dihydrotetrabenazine is reduced compared the C_(max) of the totalcombined amount of alpha-dihydrotetrabenazine andbeta-dihydrotetrabenazine at a dose of non-deuterated tetrabenazine thatyields an equivalent AUC of total combined alpha-dihydrotetrabenazineand beta-dihydrotetrabenazine and total combined deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine.

In certain embodiments, the C_(max) of the total combined amount ofdeuterated alpha-dihydrotetrabenazine and deuteratedbeta-dihydrotetrabenazine is reduced by at least 25% as compared theC_(max) of the total combined amount of alpha-dihydrotetrabenazine andbeta-dihydrotetrabenazine at a dose of non-deuterated tetrabenazine thatyields an equivalent AUC of total combined alpha-dihydrotetrabenazineand beta-dihydrotetrabenazine and total combined deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine.

In certain embodiments, the pharmaceutical composition yields, whenorally administered to a patient population, reduced interpatientvariability in AUC of the total combined amount ofalpha-dihydrotetrabenazine and beta-dihydrotetrabenazine as comparedwith non-deuterated tetrabenazine.

In certain embodiments, the pharmaceutical composition yields, whenorally administered to a patient population, reduced interpatientvariability in AUC of the total combined amount ofalpha-dihydrotetrabenazine and beta-dihydrotetrabenazine between CYP2D6poor metabolizers and CYP2D6 extensive and intermediate metabolizers ascompared with non-deuterated tetrabenazine.

In certain embodiments, disclosed herein is an extended-releasepharmaceutical formulation of d₆-tetrabenazine which permits a reductionin dose relative to non-deuterated tetrabenazine while maintaining atleast equivalent AUC of total combined alpha-dihydrotetrabenazine andbeta-dihydrotetrabenazine.

In certain embodiments, the reduction in dose is at least 30%.

In certain embodiments, the reduction in dose is at least 40%.

In certain embodiments, the extended-release pharmaceutical formulationyields an increase in half-life of total combined deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine ofat least 65% relative to the half-life of alpha-dihydrotetrabenazine andbeta-dihydrotetrabenazine resulting from the administration of anequivalent formulation comprising non-deuterated tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationyields a reduction in C_(max) of total combined deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine ofat least 50% relative to the C_(max) of alpha-dihydrotetrabenazine andbeta-dihydrotetrabenazine resulting from the administration of anequivalent formulation comprising non-deuterated tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationreduces the C_(max) of total combined deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine byat least 50% relative to the C_(max) of alpha-dihydrotetrabenazine andbeta-dihydrotetrabenazine achieved upon administration of animmediate-release formulation of tetrabenazine that yields at leastequivalent AUC of total combined alpha-dihydrotetrabenazine andbeta-dihydrotetrabenazine.

In certain embodiments, the C_(max) of total combined deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine isreduced by at least 60% relative to the C_(max) ofalpha-dihydrotetrabenazine and beta-dihydrotetrabenazine.

In certain embodiments, the C_(max) of total combined deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine isreduced by at least 70% relative to the C_(max) ofalpha-dihydrotetrabenazine and beta-dihydrotetrabenazine.

In certain embodiments, the C_(max) of total combined deuteratedalpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine isreduced by at least 75% relative to the C_(max) ofalpha-dihydrotetrabenazine and beta-dihydrotetrabenazine.

In certain embodiments, disclosed herein is an extended-releasepharmaceutical formulation comprising, in a solid dosage form for oraldelivery of between about 100 mg and about 1 g total weight:

between about 2 and about 18% of d₆-tetrabenazine;

between about 70% and about 96% of one or more diluents;

between about 1% and about 10% of a water-soluble binder; and

between about 0.5 and about 2% of a surfactant.

In certain embodiments, the total weight is about 350 mg and about 750mg.

In certain embodiments, the diluent or diluents are chosen frommannitol, lactose, and microcrystalline cellulose;

the binder is a polyvinylpyrrolidone; and

the surfactant is a polysorbate.

In certain embodiments, the extended-release pharmaceutical formulationcomprises between about 2.5% and about 11% of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 60% and about 70% mannitol or lactose;

between about 15% and about 25% microcrystalline cellulose about 5% ofpolyvinylpyrrolidone K29/32; and

between about 1 and about 2% of Tween 80.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 4% and about 9% of a d₆-tetrabenazine;

between about 60% and about 70% mannitol or lactose;

between about 20% and about 25% microcrystalline cellulose about 5% ofpolyvinylpyrrolidone K29/32; and

about 1.4% of Tween 80.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 7.5 mg of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 15 mg of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 19.5 mg of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises, in a solid dosage form for oral delivery of between about 100mg and about 1 g total weight:

between about 70 and about 95% of a granulation of d₆-tetrabenazine,wherein the d₆-tetrabenazine comprises between about 1 and about 15% ofthe granulation;

between about 5% and about 15% of one or more diluents;

between about 5% and about 20% of sustained-release polymer; and

between about 0.5 and about 2% of a lubricant.

In certain embodiments, the extended-release pharmaceutical formulationcomprises:

between about 5% and about 15% of one or more spray-dried mannitol orspray-dried lactose;

between about 5% and about 20% of sustained-release polymer; and

between about 0.5 and about 2% of a magnesium stearate.

In certain embodiments, the sustained-release polymer is chosen from apolyvinyl acetate-polyvinylpyrrolidone mixture and a poly(ethyleneoxide) polymer.

In certain embodiments, the sustained-release polymer is chosen fromKollidon® SR, POLYOX® N60K, and Carbopol®.

In certain embodiments, the sustained-release polymer is Kollidon® SR.

In certain embodiments, the sustained-release polymer is POLYOX® N60K.

In certain embodiments, the sustained-release polymer is Carbopol®.

In certain embodiments, the total weight is about 350 mg and about 700mg.

In certain embodiments, the extended-release pharmaceutical formulationcomprises from about 5 mg to about 30 mg of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 6 mg of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 12 mg of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 18 mg of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 7.5 mg d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 15 mg of d₆-tetrabenazine.

In certain embodiments, the extended-release pharmaceutical formulationcomprises about 22.5 mg of d₆-tetrabenazine.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 7.5 mg d₆-tetrabenazinewherein the C_(max) of the total combined amount of deuterateddihydrotetrabenazine is about 21.37±6.78 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 7.5 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the C_(max) of the totalcombined amount of deuterated dihydrotetrabenazine is about 21.37±6.78ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 7.5 mg d₆-tetrabenazinefor the manufacture of a medicament to treat a VMAT2-mediated diseasewherein the C_(max) of the total combined amount of deuterateddihydrotetrabenazine is about 21.37±6.78 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 176.2±69.3 hr*ng/mL.

In certain embodiments, the AUC₍₀₋₁₂₎ of the total combined amount ofdeuterated dihydrotetrabenazine is about 110.2±32.1 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 3.17±0.68 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 7.18±1.35 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 15 mg d₆-tetrabenazinewherein the C_(max) of the total combined amount of deuterateddihydrotetrabenazine is about 45.33±8.31 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 15 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the C_(max) of the totalcombined amount of deuterated dihydrotetrabenazine is about 45.33±8.31ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 15 mg d₆-tetrabenazine forthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the C_(max) of the total combined amount of deuterateddihydrotetrabenazine is about 45.33±8.31 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 408.3±147.2 hr*ng/mL.

In certain embodiments, the AUC₍₀₋₁₂₎ of the total combined amount ofdeuterated dihydrotetrabenazine is about 250.4±64.0 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 3.21±0.45 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 7.66±1.36 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 22.5 mg d₆-tetrabenazinewherein the C_(max) of the total combined amount of deuterateddihydrotetrabenazine is about 67.49±16.72 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 22.5 mg d₆-tetrabenazine for usein treatment of a VMAT2-mediated disease wherein the C_(max) of thetotal combined amount of deuterated dihydrotetrabenazine is about67.49±16.72 ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 22.5 mg d₆-tetrabenazinefor the manufacture of a medicament to treat a VMAT2-mediated diseasewherein the C_(max) of the total combined amount of deuterateddihydrotetrabenazine is about 67.49±16.72 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 610±291 hr*ng/mL.

In certain embodiments, the AUC₍₀₋₁₂₎ of the total combined amount ofdeuterated dihydrotetrabenazine is about 370±123.7 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 3.79±0.84 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 8.38±2.17 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 6 mg d₆-tetrabenazine withfood, wherein the C_(max) of the total combined amount of deuterateddihydrotetrabenazine is about 15.5±3.5 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 6 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with food and the C_(max) of the totalcombined amount of deuterated dihydrotetrabenazine is about 15.5±3.5ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 6 mg d₆-tetrabenazine forthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with food and theC_(max) of the total combined amount of deuterated dihydrotetrabenazineis about 15.5±3.5 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 132±47 hr*ng/mL.

In certain embodiments, the AUC of the total combined amount ofdeuterated dihydrotetrabenazine is about 122±46 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 3.74±0.99 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 8.64±1.84 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 12 mg d₆-tetrabenazinewith food, wherein the C_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 32.1±8.1 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 12 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with food and the C_(max) of the totalcombined amount of deuterated dihydrotetrabenazine is about 32.1±8.1ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 12 mg d₆-tetrabenazine forthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with food and theC_(max) of the total combined amount of deuterated dihydrotetrabenazineis about 32.1±8.1 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 289±115 hr*ng/mL.

In certain embodiments, the AUC of the total combined amount ofdeuterated dihydrotetrabenazine is about 279±114 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 3.90±1.27 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 9.79±2.45 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 18 mg d₆-tetrabenazinewith food, wherein the C_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 47.8±12 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 18 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with food and the C_(max) of the totalcombined amount of deuterated dihydrotetrabenazine is about 47.8±12ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 18 mg d₆-tetrabenazine forthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with food and theC_(max) of the total combined amount of deuterated dihydrotetrabenazineis about 47.8±12 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 419±165 hr*ng/mL.

In certain embodiments, the AUC_(t) of the total combined amount ofdeuterated dihydrotetrabenazine is about 407±163 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 3.63±0.85 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 10.2±3.3 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 24 mg d₆-tetrabenazinewith food, wherein the C_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 60.9±13.8 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 24 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with food and the C_(max) of the totalcombined amount of deuterated dihydrotetrabenazine is about 60.9±13.8ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 24 mg d₆-tetrabenazine forthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with food and theC_(max) of the total combined amount of deuterated dihydrotetrabenazineis about 60.9±13.8 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 580±229 hr*ng/mL.

In certain embodiments, the AUCt of the total combined amount ofdeuterated dihydrotetrabenazine is about 569±225 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 3.92±1.19 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 6.00±1.60 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 18 mg d₆-tetrabenazinewith a high-fat meal, wherein the C_(max) of the total combined amountof deuterated dihydrotetrabenazine is about 49.0±8.1 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 18 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with a high-fat meal and the C_(max) of thetotal combined amount of deuterated dihydrotetrabenazine is about49.0±8.1 ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 18 mg d₆-tetrabenazine forthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with a high-fatmeal and the C_(max) of the total combined amount of deuterateddihydrotetrabenazine is about 60.9±13.8 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 436±129 hr*ng/mL.

In certain embodiments, the AUC of the total combined amount ofdeuterated dihydrotetrabenazine is about 425±127 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 4.09±1.25 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 10.2±2.5 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising 15 mg d₆-tetrabenazinewith food, wherein the C_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 33.3±11 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 15 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with food and the C_(max) of the totalcombined amount of deuterated dihydrotetrabenazine is about 33.3±11ng/mL.

In certain embodiments, disclosed herein is the use of an extendedrelease pharmaceutical composition comprising 15 mg d₆-tetrabenazine forthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the pharmaceutical composition is administered with food and theC_(max) of the total combined amount of deuterated dihydrotetrabenazineis about 33.3±11 ng/mL.

In certain embodiments, the AUC_(inf) of the total combined amount ofdeuterated dihydrotetrabenazine is about 305±141 hr*ng/mL.

In certain embodiments, the AUC₍₀₋₁₂₎ of the total combined amount ofdeuterated dihydrotetrabenazine is about 189±65 hr*ng/mL.

In certain embodiments, the T_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 6.00 hr.

In certain embodiments, the T_(half) of the total combined amount ofdeuterated dihydrotetrabenazine is about 6.00±1.60 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising d₆-tetrabenazine withfood, wherein the ratio of fed to fasted C_(max) of the total combinedamount of deuterated dihydrotetrabenazine is greater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with food and the ratio of fed to fastedC_(max) of the total combined amount of deuterated dihydrotetrabenazineis greater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising d₆-tetrabenazine for use in themanufacture of a medicament to treat a VMAT2-mediated disease whereinthe pharmaceutical composition is administered with food and the ratioof fed to fasted C_(max) of the total combined amount of deuterateddihydrotetrabenazine is greater than 1.

In certain embodiments, the ratio of fed to fasted C_(max) is greaterthan about 1.4.

In certain embodiments, the ratio of fed to fasted C_(max) is greaterthan about 1.9.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising d₆-tetrabenazine withfood, wherein the ratio of fed to fasted AUC_(inf) of the total combinedamount of deuterated dihydrotetrabenazine is greater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with food and the ratio of fed to fastedAUC_(inf) of the total combined amount of deuterateddihydrotetrabenazine is greater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising d₆-tetrabenazine for use in themanufacture of a medicament to treat a VMAT2-mediated disease whereinthe pharmaceutical composition is administered with food and the ratioof fed to fasted AUC_(inf) of the total combined amount of deuterateddihydrotetrabenazine is greater than 1.

In certain embodiments, the ratio of fed to fasted AUC_(inf) is greaterthan about 1.1.

In certain embodiments, the ratio of fed to fasted AUC_(inf) is greaterthan about 1.2.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of an extendedrelease pharmaceutical composition comprising d₆-tetrabenazine withfood, wherein the ratio of fed to fasted AUC_(t) of the total combinedamount of deuterated dihydrotetrabenazine is greater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the pharmaceuticalcomposition is administered with food and the ratio of fed to fasted AUCof the total combined amount of deuterated dihydrotetrabenazine isgreater than 1.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising d₆-tetrabenazine for use in themanufacture of a medicament to treat a VMAT2-mediated disease whereinthe pharmaceutical composition is administered with food and the ratioof fed to fasted AUC of the total combined amount of deuterateddihydrotetrabenazine is greater than 1.

In certain embodiments, the ratio of fed to fasted AUC is greater thanabout 1.1.

In certain embodiments, the ratio of fed to fasted AUC is greater thanabout 1.2.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of multiple dosesof an extended release pharmaceutical composition comprising 7.5 mgd₆-tetrabenazine wherein the steady state C_(max) of the total combinedamount of deuterated dihydrotetrabenazine is about 31.5±8.16 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 7.5 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the steady state C_(max)of the total combined amount of deuterated dihydrotetrabenazine is about31.5±8.16 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 7.5 mg d₆-tetrabenazine for use inthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the steady state C_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 31.5±8.16 ng/mL.

In certain embodiments, the steady state AUC₍₀₋₁₂₎ of the total combinedamount of deuterated dihydrotetrabenazine is about 203±69.2 hr*ng/mL.

In certain embodiments, the steady state T_(max) of the total combinedamount of deuterated dihydrotetrabenazine is about 3.17±0.49 hr.

In certain embodiments, the steady state T_(half) of the total combinedamount of deuterated dihydrotetrabenazine is about 8.8±1.97 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of multiple dosesof an extended release pharmaceutical composition comprising 15 mgd₆-tetrabenazine wherein the steady state C_(max) of the total combinedamount of deuterated dihydrotetrabenazine is about 72.0±14.5 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 15 mg d₆-tetrabenazine for use intreatment of a VMAT2-mediated disease wherein the steady state C_(max)of the total combined amount of deuterated dihydrotetrabenazine is about72.0±14.5 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 15 mg d₆-tetrabenazine for use inthe manufacture of a medicament to treat a VMAT2-mediated diseasewherein the steady state C_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 72.0±14.5 ng/mL.

In certain embodiments, the steady state AUC₍₀₋₁₂₎ of the total combinedamount of deuterated dihydrotetrabenazine is about 443±125.8 hr*ng/mL.

In certain embodiments, the steady state T_(max) of the total combinedamount of deuterated dihydrotetrabenazine is about 2.78±0.41 hr.

In certain embodiments, the steady state T_(half) of the total combinedamount of deuterated dihydrotetrabenazine is about 9.06±2.53 hr.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disease comprising the administration of multiple dosesof an extended release pharmaceutical composition comprising 22.5 mgd₆-tetrabenazine wherein the steady state C_(max) of the total combinedamount of deuterated dihydrotetrabenazine is about 111.0±47.2 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 22.5 mg d₆-tetrabenazine for usein treatment of a VMAT2-mediated disease wherein the steady stateC_(max) of the total combined amount of deuterated dihydrotetrabenazineis about 111.0±47.2 ng/mL.

In certain embodiments, disclosed herein is an extended releasepharmaceutical composition comprising 22.5 mg d₆-tetrabenazine for usein the manufacture of a medicament to treat a VMAT2-mediated diseasewherein the steady state C_(max) of the total combined amount ofdeuterated dihydrotetrabenazine is about 111.0±47.2 ng/mL.

In certain embodiments, the steady state AUC₍₀₋₁₂₎ of the total combinedamount of deuterated dihydrotetrabenazine is about 769±357 hr*ng/mL.

In certain embodiments, the steady state T_(max) of the total combinedamount of deuterated dihydrotetrabenazine is about 3.75±0.79 hr.

In certain embodiments, the steady state T_(half) of the total combinedamount of deuterated dihydrotetrabenazine is about 9.50±2.32 hr.

In certain embodiments, the VMAT2-mediated disorder is a chronichyperkinetic movement disorder.

In certain embodiments, the VMAT2-mediated disorder is selected from thegroup consisting of Huntington's disease, hemiballismus, senile chorea,tic disorders, tardive dyskinesia, dystonia, Tourette's syndrome,depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis,and asthma.

In certain embodiments, the VMAT2-mediated disorder is Huntington'sdisease.

In certain embodiments, the VMAT2-mediated disorder is hemiballismus.

In certain embodiments, the VMAT2-mediated disorder is senile chorea.

In certain embodiments, the VMAT2-mediated disorder is a tic disorder.

In certain embodiments, the VMAT2-mediated disorder is tardivedyskinesia.

In certain embodiments, the VMAT2-mediated disorder is dystonia.

In certain embodiments, the VMAT2-mediated disorder is Tourette'ssyndrome.

In certain embodiments, the VMAT2-mediated disorder is depression.

In certain embodiments, the VMAT2-mediated disorder is cancer.

In certain embodiments, the VMAT2-mediated disorder is rheumatoidarthritis.

In certain embodiments, the VMAT2-mediated disorder is psychosis.

In certain embodiments, the VMAT2-mediated disorder is multiplesclerosis.

In certain embodiments, the VMAT2-mediated disorder is asthma.

In certain embodiments, disclosed herein is a compound which isd₆-tetrabenazine polymorph Form I.

In certain embodiments, the compound is identifiable by reference to anX-ray diffractogram that includes the major peaks, in terms of 2θ, atabout 8.3, about 11.6, about 13.9, about 20.0, and about 23.7.

In certain embodiments, the compound is identifiable by reference to anX-ray diffractogram that includes the major peaks, in terms of 2θ, atabout 8.3, about 9.8, about 11.6, about 12.0, about 13.9, about 20.0,about 22.0, about 23.7, about 24.4, about 33.5, and about 42.3.

In certain embodiments, the compound is identifiable by reference to aX-ray powder diffraction pattern substantially as shown in FIG. 9.

In certain embodiments, the compound has a differential calorimetrytrace comprising an endotherm between about 115 and about 135° C.

In certain embodiments, the compound has a differential calorimetrytrace substantially as shown in FIG. 8.

In certain embodiments, the compound has a thermogravimetric analysisprofile showing about 1.5% weight loss below about 150° C.

In certain embodiments, the compound has a thermogravimetric analysisprofile substantially as shown in FIG. 7.

In certain embodiments, disclosed herein is a process of preparing acompound which is d₆-tetrabenazine polymorph Form I, comprising the stepof cooling a saturated ethanol solution of d₆-tetrabenazine.

In certain embodiments, the d₆-tetrabenazine is dissolved in 3 volumesof ethanol, then cooled to room temperature at the rate of 20° C./hr.

In certain embodiments, the process further comprises formulating thed₆-tetrabenazine polymorph Form I to yield a pharmaceutical composition.

In certain embodiments, disclosed herein is a compound which isd₆-tetrabenazine polymorph Form I, prepared by a process comprising thestep of cooling a saturated ethanol solution of d₆-tetrabenazine.

In certain embodiments, disclosed herein is a pharmaceutical compositioncomprising d₆-tetrabenazine polymorph Form I.

In certain embodiments, disclosed herein is a pharmaceutical compositioncomprising d₆-tetrabenazine polymorph Form I, wherein thed₆-tetrabenazine polymorph Form I is prepared by a process comprisingthe step of cooling a saturated ethanol solution of d₆-tetrabenazine.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disorder comprising the administration, to a patient inneed thereof, a therapeutically effective amount of d₆-tetrabenazinepolymorph Form I.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disorder comprising the administration, to a patient inneed thereof, a therapeutically effective amount of d₆-tetrabenazinepolymorph Form I prepared by a process comprising the step of cooling asaturated ethanol solution of d₆-tetrabenazine.

In certain embodiments, disclosed herein is a compound which isd₆-tetrabenazine polymorph Form I for use in the treatment of aVMAT2-mediated disorder.

In certain embodiments, disclosed herein is a pharmaceutical compositioncomprising a compound which is d₆-tetrabenazine polymorph Form I for usein the treatment of a VMAT2-mediated disorder.

In certain embodiments, disclosed herein is the use of a compound whichis d₆-tetrabenazine polymorph Form I for the manufacture of a medicamentfor the treatment of a VMAT2-mediated disorder.

In certain embodiments, disclosed herein is the use of a pharmaceuticalcomposition comprising a compound which is d₆-tetrabenazine polymorphForm I for the manufacture of a medicament for the treatment of aVMAT2-mediated disorder.

In certain embodiments, disclosed herein is a compound which isd₆-tetrabenazine polymorph Form II.

In certain embodiments, the compound is identifiable by reference to anX-ray diffractogram that includes the major peaks, in terms of 2θ, atabout 8.3, about 11.6, about 13.9, about 20.0, and about 23.7.

In certain embodiments, the compound is identifiable by reference to anX-ray diffractogram that includes the major peaks, in terms of 2θ, atabout 8.3, about 9.8, about 11.6, about 12.0, about 13.9, about 20.0,about 22.0, about 23.7, about 24.4, about 33.5, and about 42.3.

In certain embodiments, the compound is identifiable by reference to aX-ray powder diffraction pattern substantially as shown in FIG. 12.

In certain embodiments, the compound has a differential calorimetrytrace comprising an endotherm between about 120 and about 140° C.

In certain embodiments, the compound has a differential calorimetrytrace substantially as shown in FIG. 11.

In certain embodiments, the compound has a thermogravimetric analysisprofile showing about 1.5% weight loss below about 160° C.

In certain embodiments, the compound has a thermogravimetric analysisprofile substantially as shown in FIG. 10.

In certain embodiments, disclosed herein is a process of preparing acompound which is d₆-tetrabenazine polymorph Form II, comprising thestep of evaporating a saturated methanol solution of d₆-tetrabenazine.

In certain embodiments, the methanol solution of d₆-tetrabenazine isevaporated slowly at ambient temperature and humidity.

In certain embodiments, the process further comprises formulating thed₆-tetrabenazine polymorph Form II to yield a pharmaceuticalcomposition.

In certain embodiments, disclosed herein is a compound which isd₆-tetrabenazine polymorph Form II, prepared by a process comprising thestep of evaporating a saturated methanol solution of d₆-tetrabenazine.

In certain embodiments, disclosed herein is a pharmaceutical compositioncomprising d₆-tetrabenazine polymorph Form II.

In certain embodiments, disclosed herein is a pharmaceutical compositioncomprising d₆-tetrabenazine polymorph Form II, wherein thed₆-tetrabenazine polymorph Form II is prepared by a process comprisingthe step of evaporating a saturated methanol solution ofd₆-tetrabenazine.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disorder comprising the administration, to a patient inneed thereof, a therapeutically effective amount of d₆-tetrabenazinepolymorph Form II.

In certain embodiments, disclosed herein is a method of treating aVMAT2-mediated disorder comprising the administration, to a patient inneed thereof, a therapeutically effective amount of d₆-tetrabenazinepolymorph Form II prepared by a process comprising the step ofevaporating a saturated methanol solution of d₆-tetrabenazine.

In certain embodiments, disclosed herein is a compound which isd₆-tetrabenazine polymorph Form II for use in the treatment of aVMAT2-mediated disorder.

In certain embodiments, disclosed herein is a pharmaceutical compositioncomprising a compound which is d₆-tetrabenazine polymorph Form II foruse in the treatment of a VMAT2-mediated disorder.

In certain embodiments, disclosed herein is the use of a compound whichis d₆-tetrabenazine polymorph Form II for the manufacture of amedicament for the treatment of a VMAT2-mediated disorder.

In certain embodiments, disclosed herein is the use of a pharmaceuticalcomposition comprising a compound which is d₆-tetrabenazine polymorphForm II for the manufacture of a medicament for the treatment of aVMAT2-mediated disorder.

In certain embodiments of the present invention, compositions disclosedherein comprise compounds of structural Formula I:

or a salt, solvate, or prodrug thereof, wherein:

R₁-R₂₇ are independently selected from the group consisting of hydrogenand deuterium; and

at least one of R₁-R₂₇ is deuterium.

In certain embodiments of the present invention, compositions disclosedherein comprise compounds of structural Formula II:

or a salt thereof, wherein:

R₁-R₂₈ are independently selected from the group consisting of hydrogenand deuterium;

R₂₉ is selected from the group consisting of hydrogen, deuterium,—C(O)O-alkyl and —C(O)—C₁₋₆ alkyl, or a group cleavable underphysiological conditions, wherein said alkyl or C₁₋₆ alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of —NH—C(NH)NH₂, —CO₂H, —CO₂alkyl, —SH, —C(O)NH₂, —NH₂,phenyl, —OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any R₂₉substituent is further optionally substituted with deuterium; and atleast one of R₁-R₂₉ is deuterium or contains deuterium.

In certain embodiments of the present invention, compositions disclosedherein comprise the compound:

In certain embodiments of the present invention, compositions disclosedherein comprise the compound:

In certain embodiments of the present invention, compositions disclosedherein comprise one or more of the following compounds:

In certain embodiments of the present invention, compositions disclosedherein comprise one or more of the following compounds:

In certain embodiments of the present invention, compositions disclosedherein comprise one or more of the following compounds:

In certain embodiments of the present invention, compositions disclosedherein comprise one or more of the following compounds:

Certain compounds disclosed herein may possess useful VMAT2 inhibitingactivity, and may be used in the treatment or prophylaxis of a disorderin which VMAT2 plays an active role. Thus, certain embodiments alsoprovide pharmaceutical compositions comprising one or more compoundsdisclosed herein together with a pharmaceutically acceptable carrier, aswell as methods of making and using the compounds and compositions.Certain embodiments provide methods for inhibiting VMAT2. Otherembodiments provide methods for treating a VMAT2-mediated disorder in apatient in need of such treatment, comprising administering to saidpatient a therapeutically effective amount of a compound or compositionaccording to the present invention. Also provided is the use of certaincompounds disclosed herein for use in the manufacture of a medicamentfor the prevention or treatment of a disorder ameliorated by theinhibition of VMAT2.

The compounds as disclosed herein may also contain less prevalentisotopes for other elements, including, but not limited to, ¹³C or ¹⁴Cfor carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen, and ¹⁷O or¹⁸O for oxygen.

In certain embodiments, the compound disclosed herein may expose apatient to a maximum of about 0.000005% D₂O or about 0.00001% DHO,assuming that all of the C-D bonds in the compound as disclosed hereinare metabolized and released as D₂O or DHO. In certain embodiments, thelevels of D₂O shown to cause toxicity in animals is much greater thaneven the maximum limit of exposure caused by administration of thedeuterium enriched compound as disclosed herein. Thus, in certainembodiments, the deuterium-enriched compound disclosed herein should notcause any additional toxicity due to the formation of D₂O or DHO upondrug metabolism.

In certain embodiments, the deuterated compounds disclosed hereinmaintain the beneficial aspects of the corresponding non-isotopicallyenriched molecules while substantially increasing the maximum tolerateddose, decreasing toxicity, increasing the half-life (T_(1/2)), loweringthe maximum plasma concentration (C_(max)) of the minimum efficaciousdose (MED), lowering the efficacious dose and thus decreasing thenon-mechanism-related toxicity, and/or lowering the probability ofdrug-drug interactions.

All publications and references cited herein are expressly incorporatedherein by reference in their entirety. However, with respect to anysimilar or identical terms found in both the incorporated publicationsor references and those explicitly put forth or defined in thisdocument, then those terms definitions or meanings explicitly put forthin this document shall control in all respects.

As used herein, the terms below have the meanings indicated.

The singular forms “a,” “an,” and “the” may refer to plural articlesunless specifically stated otherwise.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “n₁-n₂” is used, where n₁ and n₂ are the numbers, then unlessotherwise specified, this notation is intended to include the numbersthemselves and the range between them. This range may be integral orcontinuous between and including the end values.

The terms d₆-tetrabenazine and (+/−)-cis-d₆-tetrabenazine refer to aracemic mixture of(3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-oneand(3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,which have the following structures:

The term (+/−)-trans-d₆-tetrabenazine refers to a racemic mixture of(3R,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-oneand(3S,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one,which have the following structures:

The term “deuterium enrichment” refers to the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat the specified position. Because the naturally occurring distributionof deuterium is about 0.0156%, deuterium enrichment at any position in acompound synthesized using non-enriched starting materials is about0.0156%. The deuterium enrichment can be determined using conventionalanalytical methods known to one of ordinary skill in the art, includingmass spectrometry and nuclear magnetic resonance spectroscopy.

The term “is/are deuterium,” when used to describe a given position in amolecule such as R₁-R₂₉ or the symbol “D”, when used to represent agiven position in a drawing of a molecular structure, means that thespecified position is enriched with deuterium above the naturallyoccurring distribution of deuterium. In one embodiment deuteriumenrichment is no less than about 1%, in another no less than about 5%,in another no less than about 10%, in another no less than about 20%, inanother no less than about 50%, in another no less than about 70%, inanother no less than about 80%, in another no less than about 90%, or inanother no less than about 98% of deuterium at the specified position.

The term “isotopic enrichment” refers to the percentage of incorporationof a less prevalent isotope of an element at a given position in amolecule in the place of the more prevalent isotope of the element.

The term “non-isotopically enriched” refers to a molecule in which thepercentages of the various isotopes are substantially the same as thenaturally occurring percentages.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as D-isomers and L-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disorder” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disease”,“syndrome”, and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder or one or more of the symptomsassociated with a disorder; or alleviating or eradicating the cause(s)of the disorder itself. As used herein, reference to “treatment” of adisorder is intended to include prevention. The terms “prevent,”“preventing,” and “prevention” refer to a method of delaying orprecluding the onset of a disorder; and/or its attendant symptoms,barring a subject from acquiring a disorder or reducing a subject's riskof acquiring a disorder.

The term “therapeutically effective amount” refers to the amount of acompound that, when administered, is sufficient to prevent developmentof, or alleviate to some extent, one or more of the symptoms of thedisorder being treated. The term “therapeutically effective amount” alsorefers to the amount of a compound that is sufficient to elicit thebiological or medical response of a cell, tissue, system, animal, orhuman that is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human, monkey, chimpanzee, gorilla, and the like),rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like),lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline,and the like. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman patient.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic disorder described in thepresent disclosure. Such administration encompasses co-administration ofthese therapeutic agents in a substantially simultaneous manner, such asin a single capsule having a fixed ratio of active ingredients or inmultiple, separate capsules for each active ingredient. In addition,such administration also encompasses use of each type of therapeuticagent in a sequential manner. In either case, the treatment regimen willprovide beneficial effects of the drug combination in treating thedisorders described herein.

The term “chronic hyperkinetic movement disorders” refers to disorderscharacterized by non-purposeful, repetitive, disordered motor acts,variously termed “compulsive”, “rhythmical”, or “stereotyped.” Inhumans, chronic hyperkinetic movement disorders can be psychogenic(e.g., tics), idiopathic (as in, e.g., Tourette's syndrome andParkinson's Disease, genetic (as in, e.g., the chorea characteristic ofHuntington's Disease), infectious (as in, e.g., Sydenham's Chorea), or,as in tardive dyskinesia, drug-induced. Unless otherwise stated,“chronic hyperkinetic movement disorders” refers to and includes allpsychogenic, idiopathic, genetic, and drug-induced movement disorders.

The term “stereotyped” refers to a repeated behavior that appearsrepetitively with slight variation or, less commonly, as a complexseries of movements.

The term “VMAT2” refers to vesicular monoamine transporter 2, anintegral membrane protein that acts to transport monoamines—particularlyneurotransmitters such as dopamine, norepinephrine, serotonin, andhistamine—from cellular cytosol into synaptic vesicles.

The term “VMAT2-mediated disorder,” refers to a disorder that ischaracterized by abnormal VMAT2 activity. A VMAT2-mediated disorder maybe completely or partially mediated by modulating VMAT2. In particular,a VMAT2-mediated disorder is one in which inhibition of VMAT2 results insome effect on the underlying disorder e.g., administration of a VMAT2inhibitor results in some improvement in at least some of the patientsbeing treated.

The term “VMAT2 inhibitor”, “inhibit VMAT2”, or “inhibition of VMAT2”refers to the ability of a compound disclosed herein to alter thefunction of VMAT2. A VMAT2 inhibitor may block or reduce the activity ofVMAT2 by forming a reversible or irreversible covalent bond between theinhibitor and VMAT2 or through formation of a noncovalently boundcomplex. Such inhibition may be manifest only in particular cell typesor may be contingent on a particular biological event. The term “VMAT2inhibitor”, “inhibit VMAT2”, or “inhibition of VMAT2” also refers toaltering the function of VMAT2 by decreasing the probability that acomplex forms between a VMAT2 and a natural substrate.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without excessivetoxicity, irritation, allergic response, immunogenicity, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. Each component must be “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation. It must also be suitable for use in contact with the tissueor organ of humans and animals without excessive toxicity, irritation,allergic response, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition; Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition; Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004).

The terms “active ingredient,” “active compound,” and “active substance”refer to a compound, which is administered, alone or in combination withone or more pharmaceutically acceptable excipients or carriers, to asubject for treating, preventing, or ameliorating one or more symptomsof a disorder.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a disorder.

The term “release controlling excipient” refers to an excipient whoseprimary function is to modify the duration or place of release of theactive substance from a dosage form as compared with a conventionalimmediate release dosage form.

The term “nonrelease controlling excipient” refers to an excipient whoseprimary function do not include modifying the duration or place ofrelease of the active substance from a dosage form as compared with aconventional immediate release dosage form.

The term “prodrug” refers to a compound functional derivative of thecompound as disclosed herein and is readily convertible into the parentcompound in vivo. Prodrugs are often useful because, in some situations,they may be easier to administer than the parent compound. They may, forinstance, be bioavailable by oral administration whereas the parentcompound is not. The prodrug may also have enhanced solubility inpharmaceutical compositions over the parent compound. A prodrug may beconverted into the parent drug by various mechanisms, includingenzymatic processes and metabolic hydrolysis. See Harper, Progress inDrug Research 1962, 4, 221-294; Morozowich et al. in “Design ofBiopharmaceutical Properties through Prodrugs and Analogs,” Roche Ed.,APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drug in DrugDesign, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987;“Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al., Curr.Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. DeliveryRev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365;Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asgharnejad in“Transport Processes in Pharmaceutical Systems,” Amidon et al., Ed.,Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab.Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug DeliveryRev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12;Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled DrugDelivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8,1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130;Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al.,J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem.Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4,49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977,409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu andThakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151;Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino andBorchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv.Drug Delivery Rev. 1999, 39, 63-80; Waller et al., Br. J. Clin. Pharmac.1989, 28, 497-507.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The term “therapeutically acceptable salt,” as used herein,represents salts or zwitterionic forms of the compounds disclosed hereinwhich are therapeutically acceptable as defined herein. The salts can beprepared during the final isolation and purification of the compounds orseparately by reacting the appropriate compound with a suitable acid orbase. Therapeutically acceptable salts include acid and basic additionsalts. For a more complete discussion of the preparation and selectionof salts, refer to “Handbook of Pharmaceutical Salts, Properties, andUse,” Stah and Wermuth, Ed., (Wiley-VCH and VHCA, Zurich, 2002) andBerge et al., J. Pharm. Sci. 1977, 66, 1-19.

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

References to a compound of a formula and subgroups thereof includeionic forms, polymorphs, pseudopolymorphs, amorphous forms, and solvatesthereof. “Crystalline form,” “polymorph,” and “novel form” may be usedinterchangeably herein, and are meant to include all crystalline andamorphous forms of the compound, including, for example, polymorphs,pseudopolymorphs, solvates (including hydrates), co crystals, unsolvatedpolymorphs (including anhydrates), conformational polymorphs, andamorphous forms, as well as mixtures thereof, unless a particularcrystalline or amorphous form is referred to. In some embodiments,references to a compound include polymorphs, solvates, and/or cocrystals thereof. In some embodiments, references to a compound of aformula and subgroups thereof include polymorphs thereof. Similarly, theterm “salts” includes polymorphs of salts of compounds.

Pharmaceutical Formulations

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical composition. Accordingly, provided herein arepharmaceutical compositions which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, prodrugs, or solvates thereof, together with one or morepharmaceutically acceptable carriers thereof and optionally one or moreother therapeutic ingredients. Proper formulation is dependent upon theroute of administration chosen. Any of the well-known techniques,carriers, and excipients may be used as suitable and as understood inthe art; e.g., in Remington's Pharmaceutical Sciences. Thepharmaceutical compositions disclosed herein may be manufactured in anymanner known in the art, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or compression processes. The pharmaceuticalcompositions may also be formulated as a modified release dosage form,including delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art (see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugsand the Pharmaceutical Science, Marcel Dekker, Inc., New York, N.Y.,2002; Vol. 126).

The compositions include those suitable for oral administration. Thecompositions may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy.Typically, these methods include the step of bringing into association acompound of the subject invention or a pharmaceutically salt, prodrug,or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In certain embodiments, diluents are selected from the group consistingof mannitol powder, spray dried mannitol, microcrystalline cellulose,lactose, dicalcium phosphate, tricalcium phosphate, starch,pregelatinized starch, compressible sugars, silicified microcrystallinecellulose, and calcium carbonate.

In certain embodiments, surfactants are selected from the groupconsisting of Tween 80, sodium lauryl sulfate, and docusate sodium.

In certain embodiments, binders are selected from the group consistingof povidone (PVP) K29/32, hydroxypropylcellulose (HPC),hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), corn starch,pregelatinized starch, gelatin, and sugar.

In certain embodiments, lubricants are selected from the groupconsisting of magnesium stearate, stearic acid, sodium stearyl fumarate,calcium stearate, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, polyethylene glycol 4000-6000, talc, and glyceryl behenate.

In certain embodiments, sustained release polymers are selected from thegroup consisting of POLYOX® (poly (ethylene oxide), POLYOX® N6OK grade,Kollidon® SR, HPMC, HPMC (high viscosity), HPC, HPC (high viscosity),and Carbopol®.

In certain embodiments, extended/controlled release coating are selectedfrom a group of ethylcellulose polymers, such as ETHOCEL™ and Surelease®Aqueous Ethylcellulose Dispersions.

In certain embodiments, antioxidants are selected from a groupconsisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), sodium ascorbate, and α-tocopherol.

In certain embodiments, tablet coatings are selected from the group ofOpadry® 200, Opadry® II, Opadry® fx, Opadry® amb, Opaglos® 2, Opadry®tm, Opadry®, Opadry® NS, Opalux®, Opatint®, Opaspray®, Nutraficient®.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

Compounds may be administered orally at a dose of from 0.1 to 500 mg/kgper day. The dose range for adult humans is generally from 5 mg to 2g/day. Tablets or other forms of presentation provided in discrete unitsmay conveniently contain an amount of one or more compounds which iseffective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The precise amount of compound administered to a patient will be theresponsibility of the attendant physician. The specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diets, time of administration, route ofadministration, rate of excretion, drug combination, the precisedisorder being treated, and the severity of the disorder being treated.Also, the route of administration may vary depending on the disorder andits severity.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisorder.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be given continuouslyor temporarily suspended for a certain length of time (i.e., a “drugholiday”).

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disorder is retained.Patients can, however, require intermittent treatment on a long-termbasis upon any recurrence of symptoms.

Indications

Disclosed herein are methods of treating a VMAT2-mediated disordercomprising administering to a subject having or suspected of having sucha disorder, a therapeutically effective amount of a compound orcomposition as disclosed herein or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

VMAT2-mediated disorders, include, but are not limited to, chronichyperkinetic movement disorders, Huntington's disease, hemiballismus,senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourette'ssyndrome, depression, cancer, rheumatoid arthritis, psychosis, multiplesclerosis, asthma, and/or any disorder which can lessened, alleviated,or prevented by administering a VMAT2 inhibitor.

In certain embodiments, a method of treating a VMAT2-mediated disordercomprises administering to the subject a therapeutically effectiveamount of a compound or composition as disclosed herein, or apharmaceutically acceptable salt, solvate, or prodrug thereof, so as toaffect: (1) decreased inter-individual variation in plasma levels of thecompound or a metabolite thereof; (2) increased average plasma levels ofthe compound or decreased average plasma levels of at least onemetabolite of the compound per dosage unit; (3) decreased inhibition of,and/or metabolism by at least one cytochrome P450 or monoamine oxidaseisoform in the subject; (4) decreased metabolism via at least onepolymorphically-expressed cytochrome P450 isoform in the subject; (5) atleast one statistically-significantly improved disorder-control and/ordisorder-eradication endpoint; (6) an improved clinical effect duringthe treatment of the disorder, (7) prevention of recurrence, or delay ofdecline or appearance, of abnormal alimentary or hepatic parameters asthe primary clinical benefit, or (8) reduction or elimination ofdeleterious changes in any diagnostic hepatobiliary function endpoints,as compared to the corresponding non-isotopically enriched compound.

In certain embodiments, inter-individual variation in plasma levels ofthe compounds as disclosed herein, or metabolites thereof, is decreased;average plasma levels of the compound as disclosed herein are increased;average plasma levels of a metabolite of the compound as disclosedherein are decreased; inhibition of a cytochrome P450 or monoamineoxidase isoform by a compound as disclosed herein is decreased; ormetabolism of the compound as disclosed herein by at least onepolymorphically-expressed cytochrome P450 isoform is decreased; bygreater than about 5%, greater than about 10%, greater than about 20%,greater than about 30%, greater than about 40%, or by greater than about50% as compared to the corresponding non-isotopically enriched compound.

Plasma levels of the compound as disclosed herein, or metabolitesthereof, may be measured using the methods described by Li et al. RapidCommunications in Mass Spectrometry 2005, 19, 1943-1950; Jindal, et al.,Journal of Chromatography, Biomedical Applications 1989, 493(2), 392-7;Schwartz, et al., Biochemical Pharmacology 1966, 15(5), 645-55; Mehvar,et al., Drug Metabolism and Disposition 1987, 15(2), 250-5; Roberts etal., Journal of Chromatography, Biomedical Applications 1981, 226(1),175-82; and any references cited therein or any modifications madethereof.

Examples of cytochrome P450 isoforms in a mammalian subject include, butare not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6,CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2,CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11,CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1,CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2,CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39,CYP46, and CYP51.

Examples of monoamine oxidase isoforms in a mammalian subject include,but are not limited to, MAO_(A), and MAO_(B).

The inhibition of the cytochrome P450 isoform is measured by the methodof Ko et al. (British Journal of Clinical Pharmacology, 2000, 49,343-351). The inhibition of the MAO_(A) isoform is measured by themethod of Weyler et al. (J. Biol Chem. 1985, 260, 13199-13207). Theinhibition of the MAO_(B) isoform is measured by the method of Uebelhacket al. (Pharmacopsychiatry, 1998, 31, 187-192).

Examples of polymorphically-expressed cytochrome P₄₅₀ isoforms in amammalian subject include, but are not limited to, CYP2C8, CYP2C9,CYP2C19, and CYP2D6.

The metabolic activities of liver microsomes, cytochrome P₄₅₀ isoforms,and monoamine oxidase isoforms are measured by the methods describedherein.

Examples of improved disorder-control and/or disorder-eradicationendpoints, or improved clinical effects include, but are not limited to,change from baseline in the chorea score of the Unified Huntington'sDisease Rating Scale (UHDRS).

Examples of diagnostic hepatobiliary function endpoints include, but arenot limited to, alanine aminotransferase (“ALT”), serum glutamic-pyruvictransaminase (“SGPT”), aspartate aminotransferase (“AST” or “SGOT”),ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonialevels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” or“GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liverultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein.Hepatobiliary endpoints are compared to the stated normal levels asgiven in “Diagnostic and Laboratory Test Reference”, 4^(th) edition,Mosby, 1999. These assays are run by accredited laboratories accordingto standard protocol.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

Combination Therapy

The compounds disclosed herein may also be combined or used incombination with other agents useful in the treatment of VMAT2-mediateddisorders. Or, by way of example only, the therapeutic effectiveness ofone of the compounds described herein may be enhanced by administrationof an adjuvant (i.e., by itself the adjuvant may only have minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the patient is enhanced).

Such other agents, adjuvants, or drugs, may be administered, by a routeand in an amount commonly used therefor, simultaneously or sequentiallywith a compound as disclosed herein. When a compound as disclosed hereinis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compounddisclosed herein may be utilized, but is not required.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more anti-psychotics, including, but not limited to,chlorpromazine, levomepromazine, promazine, acepromazine,triflupromazine, cyamemazine, chlorproethazine, dixyrazine,fluphenazine, perphenazine, prochlorperazine, thiopropazate,trifluoperazine, acetophenazine, thioproperazine, butaperazine,perazine, periciazine, thioridazine, mesoridazine, pipotiazine,haloperidol, trifluperidol, melperone, moperone, pipamperone,bromperidol, benperidol, droperidol, fluanisone, oxypertine, molindone,sertindole, ziprasidone, flupentixol, clopenthixol, chlorprothixene,thiothixene, zuclopenthixol, fluspirilene, pimozide, penfluridol,loxapine, clozapine, olanzapine, quetiapine, tetrabenazine, sulpiride,sultopride, tiapride, remoxipride, amisulpride, veralipride,levosulpiride, lithium, prothipendyl, risperidone, clotiapine,mosapramine, zotepine, pripiprazole, and paliperidone.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more benzodiazepines (“minor tranquilizers”), including, butnot limited to alprazolam, adinazolam, bromazepam, camazepam, clobazam,clonazepam, clotiazepam, cloxazolam, diazepam, ethyl loflazepate,estizolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam,medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassiumclorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam, andchlordiazepoxide.

In certain embodiments, the compounds disclosed herein can be combinedwith olanzapine or pimozide.

The compounds disclosed herein can also be administered in combinationwith other classes of compounds, including, but not limited to,anti-retroviral agents; CYP3A inhibitors; CYP3A inducers; proteaseinhibitors; adrenergic agonists; anti-cholinergics; mast cellstabilizers; xanthines; leukotriene antagonists; glucocorticoidstreatments; local or general anesthetics; non-steroidalanti-inflammatory agents (NSAIDs), such as naproxen; antibacterialagents, such as amoxicillin; cholesteryl ester transfer protein (CETP)inhibitors, such as anacetrapib; anti-fungal agents, such asisoconazole; sepsis treatments, such as drotrecogin-α; steroidals, suchas hydrocortisone; local or general anesthetics, such as ketamine;norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopaminereuptake inhibitors (DARIs), such as methylphenidate;serotonin-norepinephrine reuptake inhibitors (SNRIs), such asmilnacipran; sedatives, such as diazepham; norepinephrine-dopaminereuptake inhibitor (NDRIs), such as bupropion;serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such asvenlafaxine; monoamine oxidase inhibitors, such as selegiline;hypothalamic phospholipids; endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; opioids, such as tramadol;thromboxane receptor antagonists, such as ifetroban; potassium channelopeners; thrombin inhibitors, such as hirudin; hypothalamicphospholipids; growth factor inhibitors, such as modulators of PDGFactivity; platelet activating factor (PAF) antagonists; anti-plateletagents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, andtirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine andCS-747), and aspirin; anticoagulants, such as warfarin; low molecularweight heparins, such as enoxaparin; Factor VIIa Inhibitors and FactorXa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors;vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilatand gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin,lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin,nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin,or atavastatin or visastatin); squalene synthetase inhibitors; fibrates;bile acid sequestrants, such as questran; niacin; anti-atheroscleroticagents, such as ACAT inhibitors; MTP Inhibitors; calcium channelblockers, such as amlodipine besylate; potassium channel activators;alpha-muscarinic agents; beta-muscarinic agents, such as carvedilol andmetoprolol; antiarrhythmic agents; diuretics, such as chlorothlazide,hydrochiorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichioromethiazide,polythiazide, benzothlazide, ethacrynic acid, tricrynafen,chlorthalidone, furosenilde, musolimine, bumetanide, triamterene,amiloride, and spironolactone; thrombolytic agents, such as tissueplasminogen activator (tPA), recombinant tPA, streptokinase, urokinase,prourokinase, and anisoylated plasminogen streptokinase activatorcomplex (APSAC); anti-diabetic agents, such as biguanides (e.g.metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g. troglitazone,rosiglitazone and pioglitazone), and PPAR-gamma agonists;mineralocorticoid receptor antagonists, such as spironolactone andeplerenone; growth hormone secretagogues; aP2 inhibitors;phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil,vardenafil); protein tyrosine kinase inhibitors; antiinflammatories;antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf),mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;anticancer agents and cytotoxic agents (e.g., alkylating agents, such asnitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, andtriazenes); antimetabolites, such as folate antagonists, purineanalogues, and pyrridine analogues; antibiotics, such as anthracyclines,bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such asL-asparaginase; farnesyl-protein transferase inhibitors; hormonalagents, such as glucocorticoids (e.g., cortisone),estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone anatagonists, and octreotideacetate; microtubule-disruptor agents, such as ecteinascidins;microtubule-stablizing agents, such as pacitaxel, docetaxel, andepothilones A-F; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;prenyl-protein transferase inhibitors; and cyclosporins; steroids, suchas prednisone and dexamethasone; cytotoxic drugs, such as azathiprineand cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNFantibodies or soluble TNF receptor, such as etanercept, rapamycin, andleflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxiband rofecoxib; and miscellaneous agents such as, hydroxyurea,procarbazine, mitotane, hexamethylmelamine, gold compounds, platinumcoordination complexes, such as cisplatin, satraplatin, and carboplatin.

Thus, in another aspect, certain embodiments provide methods fortreating VMAT2-mediated disorders in a subject in need of such treatmentcomprising administering to said subject an amount of a compounddisclosed herein effective to reduce or prevent said disorder in thesubject, in combination with at least one additional agent for thetreatment of said disorder. In a related aspect, certain embodimentsprovide therapeutic compositions comprising at least one compounddisclosed herein in combination with one or more additional agents forthe treatment of VMAT2-mediated disorders.

General Synthetic Methods for Preparing Compounds

The compounds as disclosed herein can be prepared by methods known toone of skill in the art and routine modifications thereof, and/orfollowing procedures similar to those described in US 20100130480(paragraphs [0093]-[0121]), US 20120003330 (paragraphs [0104]-[0162]),WO 2005077946; WO 2008/058261; EP 1716145; Lee et al., J. Med. Chem.,1996, (39), 191-196; Kilbourn et al., Chirality, 1997, (9), 59-62; Boldtet al., Synth. Commun., 2009, (39), 3574-3585; Rishel et al., J. Org.Chem., 2009, (74), 4001-4004; DaSilva et al., Appl. Radiat. Isot., 1993,44(4), 673-676; Popp et al., J. Pharm. Sci., 1978, 67(6), 871-873;Ivanov et al., Heterocycles 2001, 55(8), 1569-1572; U.S. Pat. No.2,830,993; U.S. Pat. No. 3,045,021; WO 2007130365; WO 2008058261, whichare hereby incorporated in their entirety, and references cited thereinand routine modifications thereof.

Isotopic hydrogen can be introduced into a compound as disclosed hereinby synthetic techniques that employ deuterated reagents, wherebyincorporation rates are pre-determined; and/or by exchange techniques,wherein incorporation rates are determined by equilibrium conditions,and may be highly variable depending on the reaction conditions.Synthetic techniques, where tritium or deuterium is directly andspecifically inserted by tritiated or deuterated reagents of knownisotopic content, may yield high tritium or deuterium abundance, but canbe limited by the chemistry required. Exchange techniques, on the otherhand, may yield lower tritium or deuterium incorporation, often with theisotope being distributed over many sites on the molecule.

In certain embodiments, specific examples of compounds of the presentinvention include a compound selected from the list described inparagraph [0122] of US 20100130480 and paragraph [0163] of US20120003330, which are hereby incorporated by reference.

Changes in the in vitro metabolic properties of certain of the compoundsdisclosed herein as compared to their non-isotopically enriched analogsand methods of determining such changes have been described in paragraph[0125] of US 20100130480 and paragraphs [0165]-[0185] of US 20120003330,which are hereby incorporated by reference.

The invention is further illustrated by the following examples.

FORMULATION EXAMPLES

Examples 1-5, and other Examples described herein, may be made by themethods disclosed in FIG. 1.

Example 1 15 mg d₆-Tetrabenazine Gastro-Erosional Extended Release(Small Tablet) (Formulation A)

Table 1 below discloses the elements of a 350 mg total weightgastro-erosional granulation formulation tablet comprising 15 mg (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.

TABLE 1 Material mg/tab % d₆-Tetrabenazine (milled) 15.0 4.3 MannitolPowder 185.4 53.0 Microcrystalline Cellulose 61.8 17.7 PVP K29/32 14.04.0 Tween 80 (Polysorbate 80) 3.8 1.1 Mannogem ® EZ (spray dried 31.59.0 mannitol) POLYOX ® N60K 35.0 10.0 Magnesium Stearate 3.5 1.0 Totals:350.0 100.0

d₆-Tetrabenazine (milled) is combined along with Mannitol Powder,Microcrystalline Cellulose, PVP K29/32 and Tween 80 (Polysorbate 80)into a high shear granulator and initially dry mixed at high impellerand chopper speed for 5 minutes. While mixing at high impeller speed andlow chopper speed, Purified Water is added to the mixing powders togranulate the material. Additional mixing and water addition with highimpeller and high chopper speed continues until the desired granulationend-point is achieved. The resulting granulation is wet screened tobreak up any oversized agglomerates and the material is added to a fluidbed drier and dried at 60° C. until the desired L.O.D. (loss on drying)is achieved. The dried material is sieved through a #20 mesh screen andthe oversized material is milled to a particle size of just under 20mesh in size. The dried and sized material is combined with Spray DriedMannitol and POLYOX® N6OK into a diffusive mixer (V-Blender) where it isblended for 15 minutes. Magnesium Stearate is then passed through a #30mesh screen and added to the blended material in the V-Blender. Thecontents are then lubricated for 3 minutes and discharged for tabletcompression. Using a rotary tablet press fitted with punches and dies ofthe desired shape and size, the lubricated blend is compressed intotablets of a theoretical weight of 350 mg.

Example 2 7.5 mg d₆-Tetrabenazine Gastro-Erosional Extended Release(Small Tablet) (Formulation A)

Table 2 below discloses the elements of a 350 mg total weightgastro-erosional granulation formulation tablet comprising 7.5 mgd₆-tetrabenazine.

TABLE 2 Material mg/tab % d₆-Tetrabenazine (milled) 7.5 2.1 MannitolPowder 191.0 54.6 Microcrystalline Cellulose 63.7 18.2 PVP K29/32 14.04.0 Tween 80 (Polysorbate 80) 3.8 1.1 Mannogem EZ (spray dried mannitol)31.5 9.0 POLYOX ® N60K 35.0 10.0 Magnesium Stearate 3.5 1.0 Totals:350.0 100.0

Same process as described for Example 1.

Example 3 15 mg d₆-Tetrabenazine Gastro-Retentive Extended Release(Large Tablet) (Formulation B)

Table 3 below discloses the elements of a 700 mg total weightgastro-retentive formulation tablet comprising 15 mg d₆-tetrabenazine.The gastro-retentive tablet is an elongated capsule having dimensions ofapproximately 0.7087 in. long by 0.3071 in. wide, having rounded endswith a cup depth of 0.0540 in. on each opposing side, as shown in FIG.2.

TABLE 3 Material mg/tab % d₆-Tetrabenazine (milled) 15.0 2.1 MannitolPowder 357.5 51.1 Microcrystalline Cellulose 119.0 17.0 PVP K29/32 26.03.7 Tween 80 (Polysorbate 80) 7.5 1.1 Mannogem EZ (spray dried mannitol)45.5 6.5 POLYOX ® N60K 122.5 17.5 Magnesium Stearate 7.0 1.0 Totals:700.0 100.0

Same Process as described for Example 1. But theoretical compressionweight is 700 mg.

Example 4 7.5 mg d₆-Tetrabenazine Gastro-Retentive Extended Release(Large Tablet) (Formulation B)

Table 4 below discloses the elements of a 700 mg total weightgastro-retentive formulation tablet comprising 7.5 mg d₆-tetrabenazine.The gastro-retentive tablet is an elongated capsule having dimensions ofapproximately 0.7087 in. long by 0.3071 in. wide, having rounded endswith a cup depth of 0.0540 in. on each opposing side, as shown in FIG.2.

TABLE 4 Material mg/tab % d₆-Tetrabenazine (milled) 7.5 1.1 MannitolPowder 363.0 51.9 Microcrystalline Cellulose 121.0 17.3 PVP K29/32 26.03.7 Tween 80 (Polysorbate 80) 7.5 1.1 Mannogem ® EZ (spray driedmannitol) 45.5 6.5 POLYOX ® N60K 122.5 17.5 Magnesium Stearate 7.0 1.0Totals: 700.0 100.0

Same Process as described for Example 1. But theoretical compressionweight is 700 mg.

Example 5 6 mg d₆-Tetrabenazine Immediate Release Tablet

Table 5 below discloses the elements of a 125 mg total weightimmediate-release tablet comprising 6 mg d₆-tetrabenazine.

TABLE 5 Material mg/tab % d₆-Tetrabenazine (milled) 6.0 4.8 MannitolPowder 75.0 60.0 Microcrystalline Cellulose 25.0 20.0 Sodium StarchGlycolate 2.5 2.0 PVP K29/32 6.0 4.8 Tween 80 (Polysorbate 80) 1.0 0.8Mannogem ® EZ (spray dried mannitol) 5.8 4.6 Sodium Starch Glycolate 2.52.0 Magnesium Stearate 1.2 1.0 Totals: 125.0 100.0

d₆-Tetrabenazine (milled) is combined along with Mannitol Powder,Microcrystalline Cellulose, Sodium Starch Glycolate, PVP K29/32 andTween 80 (Polysorbate 80) into a high shear granulator and initially drymixed at high impeller and chopper speed for 5 minutes. While mixing athigh impeller speed and low chopper speed, Purified Water is added tothe mixing powders to granulate the material. Additional mixing andwater addition with high impeller and high chopper speed continues untilthe desired granulation end-point is achieved. The resulting granulationis wet screened to break up any oversized agglomerates and the materialis added to a fluid bed drier and dried at 60° C. until the desiredL.O.D. (loss on drying) is achieved. The dried material is sievedthrough a #20 mesh screen and the oversized material is milled to aparticle size of just under 20 mesh in size. The dried and sizedmaterial is combined with Spray Dried Mannitol and Sodium StarchGlycolate into a diffusive mixer (V-Blender) where it is blended for 15minutes. Magnesium Stearate is then passed through a #30 mesh screen andadded to the blended material in the V-Blender. The contents are thenlubricated for 3 minutes and discharged for tablet compression. Using arotary tablet press fitted with punches and dies of the desired shapeand size, the lubricated blend is compressed into tablets of atheoretical weight of 125 mg.

Examples 6-8 6 mg, 12 mg, and 18 mg d₆-Tetrabenazine Gastro-ErosionalExtended Release (Small Tablet)

Table 6 discloses additional strengths of the sustained release 350 mgtablet formulation containing anti-oxidants and an aqueous film coating.

TABLE 6 Material mg/tab % mg/tab % mg/tab % d₆-Tetrabenazine 6.0 1.712.0 3.4 18.0 5.1 (milled) Mannitol Powder 191.3 54.7 186.9 53.4 180.551.6 Microcrystalline 64.2 18.3 62.6 17.9 63.0 18.0 Cellulose PVP K29/3214.0 4.0 14.0 4.0 14.0 4.0 BHA 0.5 0.1 0.5 0.1 0.5 0.1 Tween 80 4.0 1.14.0 1.1 4.0 1.1 (Polysorbate 80) Mannogem ® EZ 31.1 8.9 31.1 8.9 31.18.9 (spray dried mannitol) POLYOX ® N60K 35.0 10.0 35.0 10.0 35.0 10.0BHT 0.4 0.1 0.4 0.1 0.4 0.1 Magnesium Stearate 3.5 1.0 3.5 1.0 3.5 1.0Totals: 350.0 100.0 350.0 100.0 350.0 100.0 Core Tablets: 350.0 97.1350.0 97.1 350.0 97.1 Opadry II 85F184 22 10.5 2.9 10.5 2.9 10.5 2.9White Totals 360.5 100.0 360.5 100.0 360.5 100.0 (Coated Tablets):

d₆-Tetrabenazine (milled) is combined along with Mannitol Powder,Microcrystalline Cellulose, PVP K29/32, BHA and Tween 80 (Polysorbate80) into a high shear granulator and initially dry mixed at highimpeller and chopper speed for 5 minutes. While mixing at high impellerspeed and low chopper speed, Purified Water is added to the mixingpowders to granulate the material. Additional mixing and water additionwith high impeller and high chopper speed continues until the desiredgranulation end-point is achieved. The resulting granulation is wetscreened to break up any oversized agglomerates and the material isadded to a fluid bed drier and dried at 60° C. until the desired L.O.D.(loss on drying) is achieved. The dried material is sieved through a #20mesh screen and the oversized material is milled to a particle size ofjust under 20 mesh in size. The dried and sized material is combinedwith Spray Dried Mannitol, BHT and POLYOX® N6OK into a diffusive mixer(V-Blender) where it is blended for 15 minutes. Magnesium Stearate isthen passed through a #30 mesh screen and added to the blended materialin the V-Blender. The contents are then lubricated for 3 minutes anddischarged for tablet compression. Using a rotary tablet press fittedwith punches and dies of the desired shape and size, the lubricatedblend is compressed into tablets of a theoretical weight of 350 mg. Thetablet cores are then placed into a side vented, fully perforatedcoating pan where they are coated with a 20% solids dispersion ofOpadry® II 85F18422 White in Water until a theoretical weight gain of 3%is obtained.

The following examples may be made with varying amounts ofd₆-tetrabenazine, and increasing proportionally the amount of fillermaterial. Those skilled in the art will easily be able to vary theproportions of glidants, fillers/diluents, binders, disintegrants, andother ingredients in order to optimize the formulation and its method ofmanufacture.

Example 9 d₆-Tetrabenazine 50 mg Tablets

d₆-Tetrabenazine tablets of total individual weights of 250 mg andcontaining 25 mg of d₆-tetrabenazine are prepared according to the drygranulation method set out below. The tablets all containd₆-tetrabenazine and other excipients in a matrix containing the releaseretarding agent hydroxypropylmethylcellulose.

Three different formulations are employed, each differing only withrespect to the grade of hydroxypropylmethylcellulose used. The threegrades are (a) HPMC (K4M), (b) HPMC (K100 LV) and (c) HPMC (E15LV), theproperties of each of which are set out above.

TABLE 7 Ingredient Function 250 mg tablet d₆-Tetrabenazine Active agent25 mg, 20% (w/w) Lactose Diluent 103.9 mg, 31.6% (w/w) StarchBinder/Disintegrant 40.5 mg, 16.2% (w/w) (a) HPMC (K4M); orControlled-release 75 mg, 30% (w/w) (b) HPMC (K100 LV); or agent (c)HPMC (E15LV) Talc Glidant 4 mg, 1.6% (w/w)

d₆-Tetrabenazine, lactose, starch and the chosen grade of HPMC aresifted through a 30 mesh hand sieve into a suitable container. Thepowders are then mixed in a Hobart mixer for 10 minutes with the kneaderforward on slow speed. The talc is transferred through a 30 mesh handsieve and into a suitable container and the magnesium stearate wastransferred and sifted through a 60 mesh hand sieve into a suitablecontainer. The sifted talc and magnesium stearate is added tod₆-tetrabenazine, lactose, starch and HPMC in the Hobart mixer and allingredients are mixed for 2 minutes with the kneader forward on slowspeed to form the granulate. The granulate blend is then scaled inpolyethylene containers that have been double lined with polyethylenebags. The 250 mg tablets are formed by compression using an 8 mm round,flat, beveled edge punch with a single break line for both the upper andlower punches. The compressed 250 mg tablets are packed into 85 ml HDPEbottles with inner polypropylene caps containing a liner consisting ofSuryln I aluminum/polyethylene I bleached kraft membrane.

Example 10 Preparation of Tablets Containing 25 mg d₆-Tetrabenazine in aMatrix Including Polyethylene Oxide and Hydroxypropylmethylcellulose andPolyoxyalkylene Block Copolymer

For the manufacture of a 4 kg batch of 25 mg d₆-tetrabenazine tablets,half the required amount of microcrystalline cellulose, half therequired amount of lactose, half the required amount of polyethyleneoxide (PEO), half the required amount of hydroxypropylmethylcellulose(HPMC) and half the required amount of polyoxyalkylene block copolymer(Pluronic®) are filled into a Pharmatech AB-050 V Shell blender.Subsequently, d₆-tetrabenazine, with the remaining microcrystallinecellulose, lactose, PEO, HPMC and Pluronic® are added to the Blender.The blend is then mixed at 25 rpm for 10 minutes without the use of anintensifier bar. Following the 10 minutes blending, the magnesiumstearate is added to the blend, and the blend further tumbled in the VBlender for one minute at 25 rpm without the use of the intensifier. Thetablet blend is discharged from the V Blender and compressed intotablets using a Riva Pi colla Rotary tablet press model B/10 fitted with17 mm×9 mm caplet tooling. Compression parameters are adjusted in orderto achieve a tablet weight of 650 mg and hardness of 80-120N.

Example 11 Preparation of Tablets Containing d₆-Tetrabenazine in aMatrix Including Polyethylene Oxide and Hydroxypropylmethylcellulose andPolyoxyalkylene Block Copolymer—PVA Granulation Method

A. Preparation of d₆-Tetrabenazine Granules

In an alternative to the procedure described in Example 10,d₆-tetrabenazine is granulated prior to mixing with other tabletexcipients, in order to improve powder flow during compression.Granulation can be achieved through either wet or dry granulation. Inone embodiment of the invention, in order to manufacture a 30 kg batchof 50 mg d₆-tetrabenazine tablets, d₆-tetrabenazine is first wetgranulated with lactose and polyvinyl alcohol (PVA) as a binder in anAeromatic Fielder MP3/2/3 fluidized bed granulator. In brief, thegranulation binder solution is prepared by dispersing the PVA in coldwater which is subsequently heated to approximately 60° C. to solubilizethe PV A. The solution is then allowed to cool for at least 2 hours. Thegranulation solution is then top-sprayed onto an 18 kg fluidized bed ofd₆-tetrabenazine and lactose (58.41:41.59 ratio of lactose:d₆-tetrabenazine), fluidized in an Aeromatic Fielder MP3/2/3 fluidizedbed granulator with the following process conditions:

TABLE 8 Process Parameter Setting Product Temperature 25-26° C. InletAir Temperature 65° C. Air velocity 250 m3/h Atomising Air Pressure 1bar Spray Rate 70 g/min

Following application of 252 g of PVA to the fluidized bed, spraying isstopped and the granules further fluidized to dry the granulates to amoisture content of approximately 1.5% w/w.

B. Preparation of Tablets Containing d₆-Tetrabenazine

To blend the d₆-tetrabenazinegranules with the other tablet excipients,half the required amount of microcrystalline cellulose, half therequired amount of lactose, half the required amount of PEO, half therequired amount of HPMC and half the required amount of the Pluronic®are filled into a Pharmatech AB-400 V Shell blender. Subsequently, thed₆-tetrabenazinegranules, with the remaining microcrystalline cellulose,lactose, PEO, HPMC and Pluronic® are added to the Blender. The 30 kgblend is then mixed at 25 rpm for 10 minutes without the use of anintensifier bar. Following the 10 minutes blending, the magnesiumstearate is added to the blend, and the blend further tumbled in the VBlender for one minute at 25 rpm without the use of the intensifier. Thetablet blend is discharged from the V Blender and compressed intotablets using a Fette 1200 tablet press fitted with 17 mm×9 mm caplettooling. Compression parameters are adjusted in order to achieve atablet weight of 650 mg and hardness of 80-120 N.

Example 12 Preparation of Tablets Containing a d₆-Tetrabenazine:Eudragit® E Extrudate

A. Manufacture of 30:70 d₆-Tetrabenazine:Eudragit® E Extrudate

Each heating zone of an APV Baker 19 mm twin-screw extruder is heated toa target temperature of 70° C., 140° C., 140° C., 130° C., and 100° C.for each of heating zones 1, 2, 3, 4 and 5 respectively. The extrudertwin screws are then rotated at 140 rpm and a 4.6 kg blend ofd₆-tetrabenazine and Eudragit® E, preblended in a Pharmatech AB-050 Vblender for 5 minutes, is fed into the extruder hopper until all fiveheating zone temperatures are within 5° C. of the target temperature.Extrusion of the blend is continued at 140 rpm and milled extrudate iscollected on a stainless steel tray.

B. Preparation of Tablets Containing the Extrudate

In order to manufacture a 4 kg batch of 50 mg d₆-tetrabenazine tabletsincluding the melt extrusion of (A) above, half the required amount ofmicrocrystalline cellulose, half the required amount of lactose, halfthe required amount of PEO, half the required amount of HPMC and halfthe required amount of Pluronic® are filled into a Pharmatech AB-050 VShell blender. Subsequently, d₆-tetrabenazine extrudate, with theremaining microcrystalline cellulose, lactose, PEO, HPMC and Pluronic®are added to the blender. The blend is then mixed at 25 rpm for 10minutes without the use of an intensifier bar. Following the 10 minutesblending, the magnesium stearate is added to the blend, and the blend isfurther tumbled in the V Blender for one minute at 25 rpm without theuse of the intensifier. The tablet blend is discharged from the VBlender and compressed into tablets using a Riva Pi colla Rotary tabletpress model B/10 fitted with 17 mm×9 mm caplet tooling. Compressionparameters are adjusted in order to achieve a tablet weight of 650 mgand hardness of 80-120 N.

Example 13 The Formulations of Examples 13a to 13C in the Table BelowMay be Prepared by the Method Described in Example 11

Example 13A is a 650 mg 17 mm×9 mm tablet matrix formulation hardness60-80N) including 50 mg d₆-tetrabenazine, 10% w/w 5,000,000 MWPolyethylene oxide (PEO WSR Coag.), 10% w/w 4,000 cps HPMC (MethocelK4M) together with 20% polyoxyalkylene block copolymer (Pluronic® F127)as a drug release modifier.

Example 13B is a tablet identical in size and shape and hardness to 5A,has the same levels of K4M and PEO WSR Coag., but differs in that thePluronic® F127 is replaced with lactose as a drug release modifier.

Example 13C is a tablet identical in size and shape and hardness to 5A,has the same levels of Methocel K4M and PEO WSR Coag, but differs fromboth 5A and 5B in that both Pluronic® F127 and lactose are present inthe formulation.

The ingredients of the formulations of each of Examples 13A to 13C areset out in the table below as percentages.

TABLE 9 Components of Tablet Example Example Example Formulation 13A 13B13C d₆-Tetrabenazine 7.7 7.7 7.7 PEO WSR Coagulant 10 10 10 HPMC K4M 1010 10 Lactose monohydrate — 35.7 25.65 Microcrystalline Cellulose 51.335.7 25.65 Magnesium Stearate 1 1 1 Pluronic ® F127 20 — 20 TOTAL 100100 100

Example 14 Examples 14A and 14B are Similar to Those Presented inExample 13, but Use a Higher Viscosity Grade of HPMC (100,000 Cps)

TABLE 10 Components of Tablet Formulation Example 14A Example 14Bd₆-Tetrabenazine 7.7 7.7 PEO WSR Coagulant 10 10 HPMC K4M 10 10 Lactosemonohydrate 25.65 — Microcrystalline Cellulose 25.65 71.3 MagnesiumStearate 1 1 Pluronic ® F127 20 — TOTAL 100 100

Example 15

The following tables provide examples of formulations of different drugpotency including d₆-tetrabenazine and Pluronic®. The formulations shownbelow may be prepared by first granulating the drug with a binder (inthis case polyvinyl alcohol) to aid powder flow during compression.

TABLE 11 Components of Tablets 3.125 mg 6.25 mg 12.5 mg Formulation mg %mg % mg % d₆- 3.125 0.48 6.25 0.96 12.5 1.92 Tetrabenazine Polyethylene65 10 65 10 65 10 Oxide Hypomellose 65 10 65 10 65 10 Pluronic ® 130 20130 20 130 20 F127 Micro- 191.3 29.43 188.24 28.96 184.79 28.43crystalline Cellulose Lactose 191.3 29.43 188.3 28.96 184.79 28.43monohydrate Polyvinyl 0.71 0.11 0.71 0.11 1.42 0.22 Alcohol Magnesium6.5 1 6.5 1 6.5 1 Stearate TOTAL 650 100 650 100 650 100

TABLE 12 Components of Tablet 50 mg 37.5 mg 50 mg Formulation mg % Mg %Mg % d₆- 25 3.85 37.5 5.77 50 7.69 Tetrabenazine Polyethylene 65 10 6510 65 10 Oxide Hypomellose 65 10 65 10 65 10 Pluronic ® 130 20 130 20130 20 F127 Micro- 178.5 27.5 171.8 26.4 165.9 25.5 crystallineCellulose Lactose 178.5 27.5 171.8 26.4 165.9 25.5 monohydrate Polyvinyl1.68 0.26 2.52 0.39 1.68 0.26 Alcohol Magnesium 6.5 1 6.5 1 7 1 StearateTOTAL 650 100 650 100 700 100

Example 16 Gastric Retentive Formulations

The following table sets out some examples of gastric retentiveformulations according to the present invention. The followingformulations are of different drug potency and may be made by directcompression, i.e. in the absence of polyvinyl alcohol. The skilledperson will appreciate that the formulations set out below willdemonstrate that the rate and extent of drug dissolution is independentof drug potency in the formulation.

TABLE 13 Components of Tablet 3.125 mg 6.25 mg 12.5 mg Formulation mg %mg % mg % d₆- 3.125 0.48 6.25 0.96 12.5 1.93 Tetrabenazine PEO Coagulant65 10 65 10 65 10 HPMC K15M 65 10 65 10 65 10 Pluronic ® 130 20 130 20130 20 F127 Micro- 188.95 29.07 186.21 28.65 180.04 27.7 crystallineCellulose Lactose 191.4 29.44 192.1 29.55 191.0 29.38 monohydrateMagnesium 6.5 1 6.5 1 6.5 1 Stearate TOTAL 650 100 650 100 650 100

TABLE 14 Components of Tablet 25 mg 37.5 mg 50 mg Formulation mg % mg %mg % d₆- 25 3.85 37.5 5.77 50 7.15 Tetrabenazine PEO Coagulant 65 10 6510 70 10 HPMC K15M 65 10 65 10 70 10 Pluronic ® 130 20 130 20 140 20F127 Micro- 167.56 25.78 155.53 23.93 158.2 22.6 crystalline CelluloseLactose 178.44 27.45 190.47 29.30 204.79 22.26 monohydrate Magnesium 6.51 6.5 1 7 1 Stearate TOTAL 650 100 650 100 700 100

Example 17

The following table sets out some examples of formulations containingvarious combinations of d₆-tetrabenazine, PEO, HPMC and Poloxamer.

TABLE 15 Components of Tablet Formulation % w/w of 650 mg tablet A B C DE F G d₆-Tetrabenazine 7.7 7.7 7.7 7.7 7.7 7.7 7.7 PEO WSR N-60K — 20 —— — 15 — PEO WSR Coagulant 10 — 15 10 10 10 30 Methocel K100M — — 15 1510 — — Methocel K15M — — — — — — 10 Methocel K4M 10 20 — — — 15 —Pluronic ® F68 — — — 7.7 20.5 — — Pluronic ® F127 — 20 20 — — 10 20Avicel ® pH 101 51.3 15.65 20.65 58.6 63.5 41.3 15.65 Lactosemonohydrate — 15.65 20.65 — — — 15.65 Magnesium Stearate 1 1 1 1 1 1 1

Example 18

The following table sets out some examples of tablet formulationcontaining d₆-tetrabenazine:Eudragit® melt extrudates.

TABLE 16 Ingredient % w/w A B d₆-Tetrabenazine/Eudragit ® E (30:70) 25.6— extrudate d₆-Tetrabenazine/Eudragit ® 40:60 extrudate — 19.25 PEO WSRCoagulant 10 10 HPMC K4M 10 10 Lactose monohydrate 26.7 29.9Microcrystalline Cellulose 26.7 29.9 Magnesium Stearate 1 1

Example 19

The following table sets out examples of tablet formulations containinggranules including d₆-tetrabenazine and hydroxymethyl cellulose andhydroxyethylcellulose.

d₆-Tetrabenazine is blended with Methocel K100LV CR Premium, MethocelK15M Premium, Natroso1250HHX and Flowlac in a Diosna P1-6 high shearmixer for approximately 5 minutes with the chopper motor set atapproximately 600 rpm and the mixer motor set at approximately 400 rpm.The blend is granulated with 2-propanol for approximately 5 minutes andthe granules are dried in a Casburt laminar flow drying oven at atemperature of 40° C. for 18 h and screened through a 800 μm screen. Thegranules and the Ethocel 100FP are blended in a V-type PK Blendmasterwith a mixing time of approximately 5 minutes with set speeds for theblender shell and intensifier bar. Magnesium stearate is added to theblend and the mixture is further blended for approximately 1.5 min withset speed for the blender shell and the intensifier bar turned off. Theblend is compressed into tablets.

TABLE 17 Ingredient % w/w A B C D d₆-Tetrabenazine 25 25 25 25 MethocelK100LV CR Premium 7.5 15 — — (Hydroxypropylmethylcellulose) MethocelK15M Premium 8 — 15 15 (Hydroxypropylmethylcellulose) Natrosol 250 HHX(Hydroxyethylcellulose) 3.5 3.5 3.5 3.5 Flowlac 100 (Lactose) 50 50.550.5 50.5 Poloxamer F127 (Surfactant) — — — 15 Ethocel 100FP Premium(Ethylcellulose) 5 5 5 5 Magnesium Stearate 1 1 1 1

Example 20 Unitary Osmotic System Formulation

To form the following unitary osmotic system formulation, all tabletingredients are granulated except D-mannitol and lubricant. D-mannitoland lubricant are then added, and compressed using conventional means.The core is then coated with solution using the vented pan coatingprocess, to form a semipermeable membrane around core.

TABLE 18 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 22 Lactose42 Colloidal Silicon Dioxide 0.74 Polyvinyl alcohol 5.48 D-Mannitol29.04 Sodium Stearyl Fumarate 0.74 Semipermeable Membrane Ingredients %of Coating Cellulose Acetate 45 Hydroxypropyl Cellulose 40 AcetylTriethyl Citrate 5 Sodium Chloride 10 Organic Solvents (evaporated inprocess) —

Example 21 Multiparticulate Osmotic System Formulation

To form the following multiparticulate osmotic system formulation,d₆-tetrabenazine micro sphere ingredients are blended under high shearand processed using Ceform™ processing technology. Microspheres are thenplaced in a Wurster-based fluidized bed coater and sustained releasecoating applied.

TABLE 19 Microsphere Ingredients % of Sphere d₆-Tetrabenazine 22Compritol ATO 888 35 Fumaric acid (fine powder) 8 Gelucire 50/13 35 35Sustained Release Coating Ingredients % of Coating Ethyl Cellulose Prem.Std. 45 cps/10 cps 1:1 56 Hydroxypropyl cellulose 32 Talc—micronized 12Isopropranol/Acetone (evaporated in process) —

Example 22 Hydrophobic Core Controlled Release System (Lipid)

To form the following lipid-based hydrophobic core controlled releasesystem, granulate of the drug, Lubritab, Fumaric Acid, HPMC and HPC aremelted above 80 degrees C. in jacketed high shear mixer. The granulateis then congealed and screened/milled/sized; lubricant is then added andthe mixture compressed into tablets. Finally, cosmetic coat is appliedto tablets using a vented coating pan.

TABLE 20 Mini-Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 25Hydrogenated Vegetable Oil (Lubritab) 32.5 Hyprocellulo se K 1 OOLV 18.5Hydroxypropyl cellulose 18.5 Fumaric Acid 5 Magnesium Stearate 0.5Tablet Coating Ingredients % of Coating Opadry (Clear) 5% solution 100Purified Water (evaporated in process) —

Example 23 Hydrophobic Core Controlled Release System (Wax)

To form the following wax-based hydrophobic core controlled releasesystem, granulate the drug, camauba wax, citric acid and stearyl alcoholare melted at 95-100 degrees C. in jacketed high shear mixer. Thegranulate is then congealed and screened/milled/sized; lubricant is thenadded and the mixture compressed into tablets. Finally, cosmetic coat isapplied to tablets using a vented coating pan.

TABLE 21 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 29.35Carrauba Wax 35.5 Stearyl alcohol 24.65 Citric Acid 10 MagnesiumStearate 0.5 Tablet Coating Ingredients % of Coating Opadry (Clear) 5%solution 100 Purified Water (evaporated) —

Example 24 Hydrophobic Core Controlled Release System (InsolublePolymer)

To form the following insoluble polymer-based hydrophobic corecontrolled release system, d₆-tetrabenazine and silicon dioxide aregranulated using PVA solution in a fluid bed granulator using top-spraymethod. The granulate, ethyl cellulose, Ludipress, citric acid, andlubricant are then compressed into tablets using rotary compression.

TABLE 22 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 44Colloidal Silicon Dioxide 0.74 Polyvinyl alcohol 19.48 Ethyl Cellulose27 Fumaric Acid 5 Ludipress 3.04 Sodium Stearyl Fumarate 0.74 TabletCoating Ingredients % of Coating Opadry (Clear) 5% solution 100 PurifiedWater (evaporated) —

Example 25 Hydrophobic Coat (Lipid)

d₆-Tetrabenazine, citric acid and lactose are granulated with colloidalsilicon dioxide using PVA solution, under top-spray fluid bed process.Lubricant is added to granulate and compress using conventional rotaryprocess. Mini-tablets are then coated with molten lipid-based coating inWurster fluid-bed processor outfitted with hot melt coating apparatus.

TABLE 23 Mini-Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 38Lactose 55.16 Colloidal Silicon Dioxide 0.96 Polyvinyl alcohol 4.92Citric Acid 5 Sodium Stearyl Fumarate 0.96 Mini-Tablet CoatingIngredients % of Coating Glyceryl monostearate 72.25 Polyethylene Glycol8000 24.75

Example 26 Hydrophobic Coat (Wax)

d₆-Tetrabenazine and lactose are granulated with colloidal silicondioxide using PVA solution, under top-spray fluid bed process. Lubricantis added to granulate and compress using conventional rotary process.Tablets are then coated with molten wax-based coating in Wursterfluid-bed processor outfitted with hot melt coating apparatus.

TABLE 24 Mini-Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 53Lactose 40.16 Colloidal Silicon Dioxide 0.96 Polyvinyl alcohol 4.92Sodium Stearyl Fumarate 0.96 Mini-Tablet Coating Ingredients % ofCoating Hydrogenated Castor Oil (Castorwax) 72.25 Polyethylene Glycol8000 24.75

Example 27 Hydrophobic Coat (Insoluble Polymer)

d₆-Tetrabenazine and lactose are granulated with colloidal silicondioxide using PVA solution, under top-spray fluid bed process. Lubricantis added to granulate and compress using conventional rotary process.Tablets are then coated with solvent in Wurster fluid-bed processoroutfitted with hot melt coating apparatus.

TABLE 25 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 53 Lactose40.16 Colloidal Silicon Dioxide 0.96 Polyvinyl alcohol 4.92 SodiumStearyl Fumarate 0.96 Tablet Coating Ingredients % of CoatingEthylcellulose 64.09 Hydroxypropyl Cellulose 26.82 Dibutyl Sebacate 9.09Isopropanol/Acetone (evaporated) —

Example 28 Hydrophilic Core (Swellable)

All tablet ingredients except Eudragit E® and lubricant are granulatedin top spray fluid bed granulator. Eudragit E® and lubricant are thenadded and compressed into tablets using conventional means. Finally,cosmetic coat is applied to tablets using a vented coating pan.

TABLE 26 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 30.12Colloidal Silicon Dioxide 0.66 Polyvinyl alcohol 4 Hypromellose K100LV20 Eudragit RL ® powder 44.26 Sodium Stearyl Fumarate 0.96 TabletCoating Ingredients % of Coating Opadry (Clear) 5% solution 100 PurifiedWater (evaporated) —

Example 29 Hydrophilic Core (Soluble Polymer)

All tablet ingredients except HPMC and lubricant are granulated in topspray fluid bed granulator. HPMC and lubricant are then added andcompressed into tablets using conventional means. Finally, cosmetic coatis applied to tablets using a vented coating pan.

TABLE 27 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 30Colloidal Silicon Dioxide 0.66 Polyvinyl alcohol 1 HydroxypropylMethylcellulose 57.38 Ethyl cellulose 10 Sodium Stearyl Fumarate 0.96Tablet Coating Ingredients % of Coating Opadry (Clear) 5% solution 100Purified Water (evaporated) —

Example 30 Hydrophilic Coat (Swellable)

d₆-Tetrabenazine and fumaric acid with colloidal silicon dioxide aregranulated using PVA solution, under the top-spray fluid bed process.Lubricant is added to granulate and compress using conventional rotaryprocess. Coating is applied to tablets using vented coating pan.

TABLE 28 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 40.15Lactose 48.01 Colloidal Silicon Dioxide 0.96 Fumaric Acid 5 Polyvinylalcohol 4.92 Sodium Stearyl Fumarate 0.96 Tablet Coating Ingredients %of Coating Eudragit RS ® 14 Eudragit RL ® 56 Acetyl Triethyl Citrate 15Talc 15 Alcoholic/Acetone Solvents (evaporates) —

Example 31 Hydrophilic Coat (Soluble Polymer)

d₆-Tetrabenazine and lactose are granulated with colloidal silicondioxide using PVA solution, under the top-spray fluid bed process.Lubricant is added to granulate and compress using conventional rotaryprocess. A sufficient amount of aqueous coating is used to coat thetablets in a conventional vented coating pan to sustain drug release.

TABLE 29 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 36.16Lactose 60 Colloidal Silicon Dioxide 0.96 Polyvinyl alcohol 1.92 SodiumStearyl Fumarate 0.96 Tablet Coating Ingredients % of CoatingHydroxymethyl Cellulose 62 Hydroxyethyl Cellulose 38 Water (evaporated)—

Example 32 d₆-Tetrabenazine AQ Coated Tablet

d₆-Tetrabenazine, lactose, and citric acid are granulated with colloidalsilicon dioxide using PVA solution, under the top-spray fluid bedprocess. Lubricant is added to granulate and compress using conventionalrotary process. The tablet is then coated with an aqueous-based coatingdispersion/suspension in conventional vented coating pan.

TABLE 30 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 23 Lactose57.16 Colloidal Silicon Dioxide  0.96 Polyvinyl alcohol  4.92 KollidonCL  8 Citric Acid  5 Sodium Stearyl Fumarate  0.96 Tablet CoatingIngredients % of Coating Eudragit NE30D 40.03 (as dry) HydroxypropylMethylcellulose 6 cps 23.01 Polyethylene Glycol8000 11.26 Talc 400 20.26Titanium dioxide  4.31 Simethicone  1.13

Example 33 Delayed Release System (Reverse Enteric Coat, HydrophillicCore)

d₆-Tetrabenazine is granulated with colloidal silicon dioxide using PVAsolution, under top-spray fluid bed process. Hypromellose, Ludipress,and lubricant are added to the granulate and compressed using aconventional rotary process. Tablets are then coated with areverse-enteric coating in conventional vented coating pan using analcohol-based solution.

TABLE 31 Tablet Core Ingredients % of Tablet d₆-Tetrabenazine 60Colloidal Silicon Dioxide 0.74 Polyvinyl alcohol 5 H ypromellose 30Ludipress 3.52 Sodium Stearyl Fumarate 0.74 Tablet Coating Ingredients %of Coating Eudragit E100 66.9 Acetyl Triethyl Citrate 10 Talc 400 23.1

Example 34 d₆-Tetrabenazine Sustained-release (SR) formulations, 12.5 mgand 25 mg

Sustained-Release (SR) Formulation that Uses Multiparticulate to Improvesolubility/delivery of the drug, and these drug-loaded particles areincorporated and released from a matrix tablet system by a combinationof gelation and erosion of tablet. Drug-loaded particles can be ceform,shearform, extrusion-spheronization beads, layered beads, or othermultiparticulate technology.

Drug and microsphere excipients are blended, and the multiparticulatesprocessed to encapsulate the drug. Multiparticulates are then blendedwith other tablet excipients and compressed by standard means into atablet. For strengths of d₆-tetrabenazine at 12.5 mg (375 mg totaltablet weight) & 25 mg (750 mg total tablet weight), tablet sizes areformulated to be dose-proportional.

TABLE 32 Ceform Microsphere Ingredients % of Spheres d₆-Tetrabenazine 24Precirol ATO 5 (glycerol palmitostearate) 38 Milled Gelucire 50/13pellets (stearyl 38 macrogoglycerides) Tablet Excipients % of TabletDrug-loaded CEFORM Microspheres 30 Polyox (polyethyleneoxide) WSR NF75020 Encompress (dibasic calcium phosphate 49 dihydrate) MagnesiumStearate 1

Example 35 d₆-Tetrabenazine Controlled Release Formulations (7.5 mg,12.5 mg, 15 mg and 25 mg)

d₆-Tetrabenazine, lactose DC, starch 1500 & HPMC (K100LV) are sieved viaa 30 mesh screen (approximately 600 Micron) into suitable containers.The sieved powders are then blended in a suitable Mixer for 10 minutesat slow speed. The talc is sieved through a 30 mesh screen(approximately 600 Micron) and the magnesium stearate sieved through a60 mesh screen (approximately 250 Micron). The talc and magnesiumstearate are added to the mixer and blended for 2 minutes at slow speed.The powder blend is compressed on a rotary tab letting machine, usingflat bevelled edge punches.

TABLE 33 25 12.5 15 7.5 Ingredients % w/w mg mg mg mg d₆-Tetrabenazine20 10 12 6 Lactose Monohydrate DC 30.96 31.56 39.16 35.66 Starch 150016.2 25.9 16.2 25.9 Methocel K100LV 30 30 30 30 Aerosil 200 0.6 0.3 0.40.2 Talc 1.6 1.6 1.6 1.6 Magnesium Stearate 0.64 0.64 0.64 0.64

Example 36 Controlled-Release (CR) Drug Layered Bead (Multiparticulate)Examples, Solvent and Aqueous-Based

1. d₆-Tetrabenazine Sustained Release Capsules

d₆-Tetrabenazine-loaded beads may be prepared from the followingingredients.

TABLE 34 d₆-Tetrabenazine-loaded Beads % w/w d₆-Tetrabenazine 10Hypromellose 2910 (6 cps) USP 2 Triacetin USP 0.4 Citric Acid 0.6 SodiumLauryl Sulfate (SLS) 0.4 Sugar Spheres USP (20-25 mesh) 86.4 Water USP(evaporated) —

The coating composition containing the hypromellose, triacetin, citricacid, and sodium lauryl sulfate is prepared as a 10% aqueous suspension.The suspension is applied to sugar spheres using standard Wurster-basedair suspension coating using conditions suitable for Hypromellose-basedcoating (inlet target 50-70° C.).

Compression of beads into tablets (either immediate release or SR matrixtype tablets) is contemplated. d₆-tetrabenazine-loaded beads made byusing layering technique on sugar spheres are preferred, but one can usedrug-loaded granules, floatable particles, extruded/spheronized pellets,Ceform microspheres, or other multiparticulates for drug core componentas well. The typical bead size is from about 2 millimeters to about 0.1mm in diameter or longest dimension before coating. Solubizers and acids(or absence thereof) can also be used in the core or in the coatingcomponent of the drug-loaded beads.

Second-coated sustained release beads can be prepared from drug sphereshaving the following composition. The coating composition is prepared asa 15% alcohol/acetone solution that includes the two types ofethylcellulose, the hydroxypropyl cellulose, and the triethyl citrate.The solution is applied to d₆-tetrabenazine loaded sugar spheres usingstandard Wurster-based air suspension coating using conditions suitablefor Ethocel-based coatings (inlet target 45-65° C.).

The functional coating polymers for SR coating can be solvent oraqueous-based, cellulosics, methacrylics, pH independent, or pHdependent in nature. In addition to polymer application on drug layeredbeads, d₆-tetrabenazine beads manufactured by extrusion/spheronizationcan also be used as a substrate.

TABLE 35 Sustained Release (SR) d₆-Tetrabenazine Beads % w/wTetrabezaine Loaded Sugar Spheres 84.75 Ethylcellulose Std 45 Premium NF6.58 Ethylcellulose Std 10 Premium NF 2.19 Hydroxypropyl Cellulose NF4.38 Triethyl Citrate NF 2.1 Ethanol/Acetone 40:60 (evaporated) —

Immediate Release Overcoated SR Tetrabenzaine Beads (Optional)

A final immediate release (IR) coating (identical to first coatingdescribed in (A) above but employed at a different coating percentage)is optionally applied to SR d₆-tetrabenazine spheres to provide a pulsedimmediate release drug component. Percentage of dose from IR portioncould be from 0-70%, 5-50%, or 10-30%. The d₆-tetrabenazine-loaded beadscould also be supplied in a capsule containing both IR and SR beads inselected dosage fractions.

Capsule Filling of d₆-Tetrabenazine-Containing Beads (SR, SR/IR, IR)

The aqueous-based coated beads can then be filled into hard gelatincapsules of a suitable size. The capsule shell can be anypharmaceutically acceptable capsule shell but is preferably a hardgelatin capsule shell and is of suitable size for containing from about5 mg to about 30 mg of d₆-tetrabenazine. Conventional machinery andtechnique are used in filling the capsule shells. 2. d₆-TetrabenazineAqueous-based Sustained Release Capsules

d₆-Tetrabenazine-Loaded Beads May be Prepared as Disclosed Above.

Second-coated sustained release beads having the following compositioncan be prepared from drug spheres having the following composition.

TABLE 36 d₆-Tetrabenazine-Loaded Beads % w/w Tetrabezaine Loaded SugarSpheres 82 Eudragit NE30D (as dry weight) 6.4 Hypromellose 2910 6cps NF2.6 Talc 9 Purified Water (evaporated) —

The aqueous-based coating composition containing the Eudragit,hypromellose and talc can be prepared as a 20% aqueous dispersion. Thedispersion can then applied to d₆-tetrabenazine loaded sugar spheresusing standard Wurster-based air suspension coating and conditionssuitable for Eudragit NE 30D-based coatings (product temperature target25-35° C.). The functional coating polymers for SR coating can besolvent or aqueous-based, cellulosics, methacrylics, pH independent, orpH dependent in nature.

Immediate Release Overcoated SR Tetrabenzaine Beads (Optional)

A final immediate release (IR) coating (identical to first coatingdescribed in (A) above but employed at a different coating percentage)is optionally applied to SR d₆-tetrabenazine spheres to provide a pulsedimmediate release drug component. Percentage of dose from IR portioncould be from 0-70%, 5-50%, or 10-30%. The d₆-tetrabenazine-loaded beadscould also be supplied in a capsule containing both IR and SR beads inselected dosage fractions.

Capsule Filling of d₆-Tetrabenazine-Containing Beads (SR, SR/IR, IR)

The aqueous-based coated beads can then be filled into hard gelatincapsules of a suitable size. The capsule shell can be anypharmaceutically acceptable capsule shell but is preferably a hardgelatin capsule shell and is of suitable size for containing from about10 mg to about 60 mg of d₆-tetrabenazine. Conventional machinery andtechnique are used in filling the capsule shells.

Compression of beads into tablets (either immediate release or SR matrixtype tablets) is also contemplated. d₆-tetrabenazine-loaded beads usinglayering technique on sugar spheres may be used, but one canalternatively use drug-loaded granules, floatable particles,extruded/spheronised pellets, Ceform microspheres, or othermultiparticulates for drug core component as well. Typical bead size isfrom about 2 millimeters to about 0.1 mm in diameter or longestdimension before coating. Other solubizers and acids (or absencethereof) can also be used in the core or coating component of thedrug-loaded beads.

Pharmacokinetic Studies Immediate Release Formulations

A Phase 1 pharmacokinetic study was conducted in 24 healthy extensiveand intermediate CYP2D6 metabolizer volunteers receiving oral 25 mgdoses of d₆-tetrabenazine or tetrabenazine to compare the relativebioavailability and pharmacokinetics of single oral doses ofd₆-tetrabenazine and its metabolites d₆-α-HTBZ and d₆-β-HTBZ with theirnon-deuterated equivalents (tetrabenazine, α-HTBZ and β-HBZ) as well asthe corresponding O-desmethyl metabolites of α-HTBZ and β-HTBZ. Subjectsreceived a single oral dose of 25 mg of d₆-tetrabenazine ortetrabenazine after an overnight fast, as a powder in capsule, in Period1 and following washout of at least 7 days. Patients were crossed overto receive the other treatment in Period 2. In each period, plasmasamples were collected over 72 hours post-dose.

The in vivo metabolism of α-HTBZ and β-HTBZ was significantly attenuatedfollowing d₆-tetrabenazine administration, resulting in a more thandoubling of the systemic exposure to total (α+β)-HTBZ when compared toexposure following tetrabenazine administration. Pharmacokinetic resultsare shown below in Table 37 and FIG. 3, results are presented as Mean (%CV) for C_(max), AUC and t_(1/2) (AUC_(last) presented for parent drugas AUC_(inf) not calculable), and as Mean (range) for Tmax. Theincreased exposure was principally attributable to increases inhalf-life and was associated with proportional reductions in O-desmethylmetabolites of HTBZ.

TABLE 37 Summary of Pharmacokinetic Parameters after Single Oral Dose ofd₆-Tetrabenazine 25 mg or Tetrabenazine 25 mg d₆- d₆- (α + β)- (α + β)-Parameter Tetrabenazine Tetrabenazine HTBZ HTBZ C_(max) 0.327 0.314 74.661.6 (ng/mL) (85.3) (111.0) (37.1) (38.2) T_(max) (hr) 0.67 0.67 1.501.00 (0.33-1.50) ^(a) (0.33-2.00) ^(b) (0.67-2.00) (0.67-2.50) AUC_(inf)0.30 0.26 542 261 (ng hr/mL) (101.9) (168.2) (53.8) (69.6) t_(1/2) (hr)N.C. N.C. 8.62 4.82 (38.2) (50.8) Parameter d₆-α-HTBZ α-HTBZ d₆-β-HTBZβ-HTBZ C_(max) 46.1 41.2 29.6 20.5 (ng/mL) (30.4) (36.0) (49.4) (51.5)T_(max) (hr) 1.5 1.00 1.50 1.00 (0.67-2.52) (0.67-2.00) (0.67-2.50)(0.67-2.50) AUC_(inf) 373 189 171 74.0 (ng hr/mL) (39.3) (59.2) (94.0)(99.5) t_(1/2) (hr) 8.97 5.47 5.00 2.95 (34.7) (51.4) (79.7) (57.2)d₃-9-O- 9-O- d₃-9-O- 9-O- desmethyl- desmethyl- desmethyl- desmethyl-Parameter α-HTBZ ^(e) α-HTBZ ^(f) β-HTBZ ^(e) β-HTBZ ^(f) C_(max) 2.155.05 6.29 15.7 (ng/mL) (52.5) (38.6) (31.7) (27.3) T_(max) (hr) 3.022.00 1.75 1.75 (1.50-16.0) (0.67-4.00) (0.67-8.02) (0.67-4.00)AUC_(last) 21.0 42.5 92.4 205 (ng hr/mL) (37.2) (47.1) (29.6) (32.6)AUC_(inf) N.C. 49.9 114 220 (ng hr/mL) (59.8) ^(c) (24.6) ^(d) (31)t_(1/2) (hr) N.C. 6.95 16.9 16.2 (47.1) ^(c) (31.4) ^(d) (22.9)Parameter d₃-10-ODM-β-HTBZ ^(e) 10-ODM-β-HTBZ ^(f) C_(max) 0.59 1.63(ng/mL) (73.9) (37.2) T_(max) (hr) 1.50 1.25 (1.00-2.00) ^(c)(0.67-2.90) AUC_(last) 0.7 3.0 (ng hr/mL) (111) (46.3) AUC_(inf) N.C.N.C. (ng hr/mL) t_(1/2) (hr) N.C. N.C. ^(a) n = 18 ^(b) n = 15 ^(c) n =8 ^(d) n = 12 ^(e) Test article: d₆-Tetrabenazine ^(f) Test article:Tetrabenazine N.C. = not calculable

Relative Bioavailability of Deuterated and Non-Deuterated Metabolites.

The effect of deuteration on key pharmacokinetic parameters wasevaluated by comparing d₆-tetrabenazine (test) to tetrabenazine(reference) using an analysis of variance (ANOVA) model for a two-periodcrossover including factors Sequence, Treatment, Period and Subject.Pharmacokinetic parameters were log-transformed before analysis. Pointestimates and 2 one-sided 95% confidence limits (CL) were constructedand then back-transformed. The estimate of the effect of deuteration onthese parameters for α-HTBZ, β-HTBZ and total (α+β)-HTBZ is shown inTable 38.

TABLE 38 Ratio of Mean Pharmacokinetic Parameters After Single Oral Doseof d₆-Tetrabenazine 25 mg or Tetrabenazine 25 mg Ratio of Lower Upper LSMeans 95% CL 95% CL Analyte Parameter (%) (%) (%) α-HTBZ C_(max) (ng/mL)113.7 100.0 129.3 AUC_(last) 214.8 195.1 236.7 (hr*ng/mL) AUC_(inf)213.6 194.0 235.0 (hr*ng/mL) t_(1/2) (hr) 174.7 156.5 195.0 β-HTBZC_(max) (ng/mL) 145.8 126.2 168.5 AUC_(last) 240.1 219.9 262.2(hr*ng/mL) AUC_(inf) 235.8 216.7 256.5 (hr*ng/mL) t_(1/2) (hr) 153.0138.3 169.3 Total C_(max) (ng/mL) 121.7 106.3 139.2 (α + β)- AUC_(last)222.5 206.0 240.3 HTBZ (hr*ng/mL) AUC_(inf) 222.2 205.9 239.7 (hr*ng/mL)t_(1/2) (hr) 188.0 167.4 211.1

Extended Release Formulations

A Phase 1 randomized, open, 5-way crossover study was conducted inhealthy CYP2D6 extensive metabolizers (EMs) and intermediatemetabolizers (IMs). Subjects (n=24 total) were administered a singledose of either Formulation A (15 mg d₆-tetrabenazine in a round tablet,350 mg), Formulation B (15 mg d₆-tetrabenazine in an oval tablet, 700mg), or tetrabenazine (25 mg in an immediate release tablet).Administration was either in a fasted state (at least 10 hours) or in afed state (post-high-fat and high-calorie meal/breakfast following afast of at least 10 hours). Blood samples for measurements of plasmaanalytes including total (α+β)-HTBZ were taken at periodic intervals upto 24 hours post dose. Results are shown in FIG. 3 and below in Table39, showing pharmacokinetic parameters for d₆-Total (α+β)-HTBZ or TotalHTBZ. In vitro, Formulation A released a substantial portion ofd₆-tetrabenazine by approximately 4 hours; Formulation B released asubstantial portion d₆-tetrabenazine by approximately 8 hours. In eachcell, the top value is the mean, the middle value is the standarddeviation, and the bottom is the percentage interpatient variability (%CV).

TABLE 39 Pharmacokinetic Parameters After Single Oral Dose ofd₆-Tetrabenazine Extended Release Formulations or Tetrabenazine 25 mgTBZ- A-Fasted B-Fasted A-Fed B-Fed Fasted 15 mg 15 mg 15 mg 15 mg 25 mgC_(max) 22.52 14.49 33.32 28.72 65.14 (ng/mL) (8.18) (6.02) (11.09)(11.33) (21.25) 36.3 41.6 33.3 39.5 32.6 T_(max) (hr) 2.65 4.21 4.796.27 1.13 (1.85) (2.84) (1.70) (1.94) (0.37) 69.9 67.4 35.5 30.9 32.8T_(half) (hr) 9.35 10.03 6.99 6.98 4.46 (2.25) (1.61) (1.59) (1.33)(2.53) 24.1 16.0 22.7 19.1 56.7 AUC_(t) 262.3 241.9 295.1 305.6 251.0(hr*ng/mL) (119.4) (118.5) (139.3) (143.8) (172.8) 45.5 49.0 47.2 47.168.9 AUC_(inf) 272.7 258.7 304.1 314.5 257.0 (hr*ng/mL) (122.0) (122.3)(140.9) (145.5) (177.0) 44.7 47.3 46.3 46.3 68.9

Relative Bioavailability of Deuterated and Non-Deuterated Metabolites.

In an additional analysis, an analysis of variance was conducted tocompare the relative pharmacokinetic properties of the extended-releaseformulations A and B administered in either a fasted or fed state.Administration of d₆-tetrabenazine 15 mg with either ER formulationachieved systemic exposure to total (α+β)-HTBZ that was comparable to orslightly higher than that after tetrabenazine 25 mg, but with C_(max)values that were markedly lower. Half lives of the deuterated HTBZmetabolites were longer than those observed for tetrabenazine. Similarfindings were observed for α-HTBZ, and β-HTBZ. The ratio of LS means(test/reference) for total HBTZ is given as a percentage below in Table40. ND indicates no data.

TABLE 40 Pharmacokinetic Parameters After Single Oral Dose ofd₆-Tetrabenazine Extended Release Formulations A-Fasted A-Fed B-FastedB-Fed C_(max) (ng/mL) 34.4 51.4 21.7 43.3 AUC_(t) (hr*ng/mL) 113.5 ND102.6 ND AUC_(inf) (hr*ng/mL) 115.5 127.7 105.6 131.2 t_(1/2) (hr) 222.7167.6 240.4 168.8

An additional Phase 1 study was conducted in healthy CYP2D6 extensivemetabolizers (EMs) and intermediate metabolizers (IMs). Subjects (n=30total) were administered a single dose of Formulation A (6, 12, 18, or24 mg d₆-tetrabenazine in a round tablet. Administration was either in afed state (post-standard or high-fat meal). Blood samples formeasurements of plasma analytes including total (α+β)-HTBZ were taken atperiodic intervals up to 24 hours post dose. Results are shown below inTable 41, showing pharmacokinetic parameters for d₆-Total (α+β)-HTBZ orTotal HTBZ. In each cell, the top value is the mean, the middle value isthe standard deviation, and the bottom is the percentage interpatientvariability (% CV).

TABLE 41 Pharmacokinetic Parameters After Single Oral Dose ofd₆-Tetrabenazine Extended Release Formulation 6 mg- 12 mg- 18 mg- 24 mg-18 mg- Standard Standard Standard Standard High-fat Meal Meal Meal MealMeal C_(max) 15.5 32.1 47.8 60.9 49.0 (ng/mL) (3.5) (8.1) (12.0) (13.8)(8.1) 22 25 25 23 17 T_(max) (hr) 3.74 3.90 3.63 3.92 4.09 (0.99) (1.27)(0.85) (1.19) (1.25) 26 33 23 30 30 T_(half) (hr) 8.64 9.79 10.2 10.410.2 (1.84) (2.45) (3.3) (2.4) (2.5) 21 25 33 23 24 AUC_(t) 122 279 407569 425 (hr*ng/mL) (46) (114) (163) (225) (127) 38 41 40 40 30 AUC_(inf)132 289 419 580 436 (hr*ng/mL) (47) (115) (165) (229) (129) 35 40 39 3930

Steady-State Pharmacokinetics

An open-label single and multiple ascending dose study ofd₆-tetrabenazine ER in comparison to tetrabenazine was performed.Subjects (n=12) were administered either d₆-tetrabenazine ER at dosagelevels of 7.5 mg, 15 mg, and 22.5 mg, or tetrabenazine (25 mg in animmediate release tablet). Administration was by a single dose orrepeated doses up to 3 days twice daily. Blood samples for measurementsof plasma total (α+β)-HTBZ were taken at periodic intervals up to 24hours post dose. Single dose results are shown in FIG. 3 and below inTable 42, showing pharmacokinetic parameters for d₆-Total (α+β)-HTBZ orTotal HTBZ. In each cell, the top value is the mean, the middle value isthe standard deviation, and the bottom is the percentage interpatientvariability (% CV).

TABLE 42 Pharmacokinetic Parameters After a Single Oral Dose ofd₆-Tetrabenazine Extended Release Formulation d₆-Tetrabenazined₆-Tetrabenazine d₆-Tetrabenazine ER ER ER 7.5 mg 15 mg 22.5 mg TBZ-25mg C_(max) (ng/mL) 21.37 45.33 67.49 55.49 6.78 8.31 16.72 21.88 31.7%18.3% 24.8% 39.4% T_(max) (hr) 3.17 3.21 3.79 1.42 0.68 0.45 0.84 0.6321.6% 14.0% 22.2% 44.7% T_(half) (hr) 7.18 7.66 8.38 5.60 1.35 1.36 2.171.98 18.8% 17.7% 22.0% 35.3% AUC₍₀₋₁₂₎ (hr*ng/mL) 110.2 250.4 370 247.032.1 64.0 123.7 136.3 29.2% 25.6% 33.4% 55.2% AUC_(inf) (hr*ng/mL) 176.2408.3 610 322.0 69.3 147.2 291 220.8 39.4% 36.1% 47.0% 68.6%

Steady-state dosing results are shown in FIG. 3 and below in Table 43,showing pharmacokinetic parameters for d₆-Total (α+β)-HTBZ or TotalHTBZ. In each cell, the top value is the mean, the middle value is thestandard deviation, and the bottom is the percentage interpatientvariability (% CV).

TABLE 43 Pharmacokinetic Parameters After Multiple Oral Doses ofd₆-Tetrabenazine Extended Release Formulation d₆-Tetrabenazined₆-Tetrabenazine d₆-Tetrabenazine ER ER ER 7.5 mg 15 mg 22.5 mg TBZ-25mg C_(max) (ng/mL) 31.5 72.0 111.0 94.9 8.16 14.5 47.2 29.16 26% 21% 43%  31% T_(max) (hr) 3.17 2.78 3.75 1.34 0.49 0.41 0.79 0.62 16% 15% 21%  46% T_(half) (hr) 8.8 9.06 9.50 6.30 1.97 2.53 2.32 1.97 22% 28% 21%31.2% AUC₍₀₋₁₂₎ (hr*ng/mL) 203 443 769 415.8 69.2 125.8 357 237.9 34%28% 46% 57.2%

Polymorphs Example 37 d₆-Tetrabenazine Form I

d₆-Tetrabenazine was dissolved in 3 volumes of ethanol, then the mixturewas heated until the solid was dissolved. The solution was stirred andcooled to room temperature at the rate of 20° C./h. Then the mixture wasstirred at 0° C. for 1 h. The precipitated solid was isolated byfiltration and dried under to give d₆-tetrabenazine, Form I.Characteristic X-ray powder diffraction peaks are shown in Table 44 andFIG. 9.

TABLE 44 Pos. [°2 Th.] d-spacing Rel. Int. [%] 5.990 14.74211 1.7 6.53213.52030 100.0 8.197 10.77773 3.8 8.697 10.15873 12.0 10.810 8.1780622.8 12.180 7.26081 42.8 12.658 6.9780 6.8 12.995 6.0737 35.2 13.2906.65688 15.1 14.155 6.25199 11.0 14.426 6.13491 30.5 15.416 5.74318 8.016.271 5.44309 4.0 17.098 5.18171 12.0 17.396 5.09370 6.0 18.038 4.9139514.7 18.661 4.75116 7.6 19.526 5.54253 6.6 19.968 4.44291 14.9

A sample of d₆-tetrabenazine Form I was analyzed by thermogravimetricanalysis. The results are shown in FIG. 7. A sample of d₆-tetrabenazineForm I was analyzed by differential scanning calorimetry. The resultsare shown in FIG. 8.

Example 38 d₆-Tetrabenazine Form II

d₆-Tetrabenazine was dissolved in methanol and precipitated by slowevaporation at ambient temperature and humidity to gived₆-tetrabenazine, Form II. Characteristic X-ray powder diffraction peaksare shown in Table 45 and FIG. 12.

TABLE 45 Pos. [°2 Th.] d-spacing Rel. Int. [%] 8.2971 10.65669 100.009.7596 9.06279 1.08 11.5878 7.63674 2.51 11.9854 7.38428 1.40 13.93956.35319 2.20 16.8229 5.27022 0.39 17.7086 5.00859 0.65 20.0394 4.430992.70 20.6309 4.30526 0.65 22.0276 4.03532 1.57 22.9053 3.88265 0.8423.3083 3.81642 0.74 23.6760 3.75798 2.83 24.4118 3.64636 1.01 27.48393.24535 0.36 33.5077 2.67442 1.24 39.6425 2.27355 0.29 42.2841 2.137431.37 43.8696 2.06210 0.25

A sample of d₆-tetrabenazine Form II was analyzed by thermogravimetricanalysis. The results are shown in FIG. 10. A sample of d₆-tetrabenazineForm II was analyzed by differential scanning calorimetry. The resultsare shown in FIG. 11.

From the foregoing description, one skilled in the art can ascertain theessential characteristics of this invention, and without departing fromthe spirit and scope thereof, can make various changes and modificationsof the invention to adapt it to various usages and conditions.

What is claimed is:
 1. A pharmaceutical composition comprising, in asolid dosage form for oral delivery of between about 100 mg and about 1g total weight: between about 2% and about 18% of d₆-tetrabenazine;between about 60% and about 70% mannitol; between about 15% and about25% microcrystalline cellulose; between about 1% and about 10% of apolyvinylpyrrolidone; between about 0.5% and about 2% of a polysorbate;between about 5% and about 20% of a poly(ethylene oxide) polymer; andbetween about 0.5% and about 2% of magnesium stearate.
 2. Thepharmaceutical composition as recited in claim 1 wherein saidpolyvinylpyrrolidone is PVP K29/32.
 3. The pharmaceutical composition asrecited in claim 1 wherein said polysorbate is Tween
 80. 4. Thepharmaceutical composition as recited in claim 1 wherein saidpoly(ethylene oxide) polymer is POLYOX® N60K.
 5. The pharmaceuticalcomposition as recited in claim 1 further comprising an anti-oxidant. 6.The pharmaceutical composition as recited in claim 5 wherein saidanti-oxidant is selected from the group consisting of butylatedhydroxyanisole and butylated hydroxytoluene.
 7. The pharmaceuticalcomposition as recited in claim 1 further comprising an anti-oxidant. 8.The pharmaceutical composition as recited in claim 1 further comprisingan aqueous film coating.
 9. The pharmaceutical composition as recited inclaim 8 wherein said aqueous film coating comprises Opadry® II 85F18422.10. The pharmaceutical composition as recited in claim 1 wherein thetotal weight is about 350 mg.
 11. The pharmaceutical composition asrecited in claim 1 comprising from about 5 mg to about 30 mg ofd₆-tetrabenazine.
 12. The pharmaceutical composition as recited in claim11 comprising about 6 mg of d₆-tetrabenazine.
 13. The pharmaceuticalcomposition as recited in claim 11 comprising about 12 mg ofd₆-tetrabenazine.
 14. The pharmaceutical composition as recited in claim11 comprising about 15 mg of d₆-tetrabenazine.
 15. The pharmaceuticalcomposition as recited in claim 11 comprising about 18 mg ofd₆-tetrabenazine.
 16. The pharmaceutical composition as recited in claim1 comprising, in a solid dosage form for oral delivery of about 350 mgtotal weight: about 15 milligrams d₆-tetrabenazine; about 62.0%mannitol; about 17.7% microcrystalline cellulose; about 4.0% of PVPK29/32; about 1.1% of Tween 80; about 10.0% of POLYOX® N60K; and about1.0% of magnesium stearate.
 17. The pharmaceutical composition asrecited in claim 16 further comprising an anti-oxidant selected from thegroup consisting of butylated hydroxyanisole and butylatedhydroxytoluene.
 18. The pharmaceutical composition as recited in claim17 further comprising an aqueous film coating.
 19. The pharmaceuticalcomposition as recited in claim 18 wherein said aqueous film coatingcomprises Opadry® II 85F18422.
 20. The pharmaceutical composition asrecited in claim 1 comprising, in a solid dosage form for oral deliveryof about 350 mg total weight: about 6 milligrams d₆-tetrabenazine; about63.6% mannitol; about 18.3% microcrystalline cellulose; about 4.0% ofPVP K29/32; about 1.1% of Tween 80; about 10.0% of POLYOX® N60K; about1.0% of magnesium stearate; about 0.1% of butylated hydroxyanisole; andabout 0.1% of butylated hydroxytoluene. 21-28. (canceled)